Beruflich Dokumente
Kultur Dokumente
Listofcontents,abbreviationsanddeclarations
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
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
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
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
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
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
Listofcontents,abbreviationsanddeclarations
Listofcontents,abbreviationsanddeclarations
10
DECLARATION
Noportionoftheworkreferredtointhisthesishasbeensubmittedinsupportofan applicationforanotherdegreeorqualificationofthisoranyotherUniversityorother Instituteoflearning.
COPYRIGHTDECLARATION
Copyrightinthetextofthethesis/dissertationrestswiththeauthor.Copies(byany process)eitherinfull,orofextracts,maybemadeonlyinaccordancewithinstructions givenbytheAuthorandlodgedintheJohnRylandsUniversityLibraryofManchester. DetailsmaybeobtainedfromtheLibrarian.Thispagemustformpartofanysuchcopies made.Furthercopies(byany process)ofcopiesmadeinaccordancewithsuch instructionsmaynotbemadewithoutthepermission(inwriting)oftheAuthor.
Listofcontents,abbreviationsanddeclarations
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ACKNOWLEDGMENTS
OvertheseveralyearsithastakentowritethisthesisIhavemanyindividualstothank. 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,BritainwasdependentonGermanyfor
1 syntheticdrugs,aswellasmanyalkaloidsandchemicalintermediates. HowdidBritish
pharmaceuticalfirmssynthesisecomplexessentialdrugswithinweeksoftheoutbreakof
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
13
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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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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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,therehasnotyetbeenageneralsynthesisofhowthemodernBritishpharmaceutical
2 industrydeveloped,andoftheexternalfactorsinvolved. Therehavebeenaccountsof
individualcompanieswithlongpedigreesinpharmacy,butnonefocusingonchemistryand
3 largescaledrugsynthesis. Thehistoriographyofdrugshasfocusedalmostexclusivelyon
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.
14
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
15
majornaturaldrugssuchasinsulinandpenicillin,ratherthandrugsinventedbythe pharmaceuticalindustry.ThesehistoriesthereforegivenoinsightintohowBritish
4 companiesdevelopedproductsoftheirownresearch,orthestrategiestheyfollowed.
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
15
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
16
Thepoliticsandmarketingofdrugshavedominatedmorerecentinvestigations.The
7 OfficeofHealthEconomics hassupportedtheindustry,whilemanyauthorshavebeen 8 9 criticalofdrugsafety, pricing ,promotion,animaltesting,ormorerecently,policiesin 10 developingandmarketingdrugsfortheThirdWorld, oftenfrompreconceived
11 positions.
Economichistorianshavefrequentlydescribedthedevelopmentof technologyinindustriesinwhichchangewassimpleandhaveneglectedthe
PatentsandtheChemicalIndustry:ToolsofBusinessStrategyinJ.Liebenau(ed.),The ChallengeofNewTechnology:InnovationinBritishBusiness(Aldershot:Gower,1988).
7
A.Chetley,ProblemDrugs(London:AtlanticHighlands,N.J.ZedBooks,1995).
L.Marsa,PrescriptionforProfits:HowthePharmaceuticalIndustryBankrolledthe UnholyMarriagebetweenScienceandBusiness(NewYork:Scribner,1997).
10
L.F.Haber,TheChemicalIndustry19001930:InternationalGrowthand TechnologicalChange(Oxford:ClarendonPress,1971):7.
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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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,allowingmetofocusprimarilyonthechemicaldevelopmentswithinthe
15 laboratoriesinwhichnewdrugswerecreatedtoreplacenaturalextracts. Otherhistories 16 havefocusedonHenryWellcomehimself.
13 14
L.F.Haber,(1958):ix.
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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Nineteenthcenturypharmaceuticalmanufacturingexistedintwomainformsinallof themajorcountries.Ethicaldrugfirmsmanufacturedsciencebaseddrugsforphysicians, withemphasisonactiveprinciples,anddifferentiatedtheirproductsfromotherfirmsbased onthenoveltyoftheirtabletsorpills,theirstrength,thelevelofimpurities,theirbenefits andtolerance,andlaterpharmacologicalexperimentsandclinicalexperience. Patent medicineswereadvertiseddirectlytopatients,withfancifulnamesandextravagantclaims. Formanyyearsthetwosystemscoexistedbutthemedicalprofessionbecameincreasingly criticaloftheunsubstantiatedclaimsofpatentmedicines.TheBritishMedical AssociationsSecretremedycampaignsin190709highlightedtheunreliabilityofpatent medicines,andconcernsaboutadulteratedmedicinesinAmericaledtolegislativecontrols
17 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. MuchoftheresearchonGermanfirmsfocusesontheevolutionofchemical
18 manufacturefromdyesandstatesupport. IntheEnglishliterature,anexcellentinsight
intothecollaborationofindustrywithPaulEhrlichandotheracademicscientistsisgivenin
17
T.Lenoir,RevolutionfromAbove:TheRoleoftheStateinCreatingtheGerman ResearchSystem,18101910TheAmericanEconomicReview(May1998):2227.
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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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
SwannreportedthatEdwardKendallleftthelaboratoryatParkeDavisin1910becauseof
23 thelackofascholarlyatmosphereandbecausehewastreatedlikeafactoryworker.
Swannarguedthatthefoundationsfortheriseofindustrialpharmaceuticalresearchinthe interwarperiodwereprogressinnaturalsciences,aninstitutionalframework,which
19 20
E.Bumler,PaulEhrlich,ScientistforLife (NewYork:Holmes&Meier,1984).
JohnP.Swann,AcademicScientistsandthePharmaceuticalIndustry:Cooperative ResearchinTwentiethCenturyAmerica(Baltimore:JohnHopkinsPress,1988):34.
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
20
facilitateditsapplication,andthewillingnessofindustrialiststorecognisetheimportanceof scienceandofscientiststoworkwithindustrialfirms.
24 25 LikeLiebenau ,Swann concludedthatinBritainupto1920,researchdeveloped
theimportanceofcollaborationswithexternalpharmacologistsandpharmacistsin WisconsinandPhiladelphia.28
24
JohnP.Swann,AcademicScientistsandthePharmaceuticalIndustry:Cooperative ResearchinTwentiethCenturyAmerica(Baltimore:JohnHopkinsPress,1988):34.
26
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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29 ForEngland,Tansey gavethebackgroundtothedevelopmentoflaboratoriesat
&HanburysdidnotseethemselvescompetingdirectlywithGermanfirms,evenafterthey
31 developedlaboratoriesandthisisapointthatIwilldevelop.Quirke emphasisedthe
SwannrecognisedthatsomeAmericanfirmsbecameimportantpoolsofscientists, collaboratingwithpharmacologistsinuniversitiesandmedicalschoolsintheinterwar
33 period. TheexamplesgivenincludedEliLilly,Merck,ParkeDavis,AbbottandE.R.
29
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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companyperspectivethebestknownarethecollaborationsofEliLillywithToronto UniversityregardinginsulinandthecollaborationofHarvardUniversitywithseveralfirms withlivertherapyforperniciousanaemia.Swannaddressedsomeofthedifficultiesof collaborativeworkincludingproprietaryinterests,sharinginformationwithoutsiders, publicationsandpatenting,butconcludedthatthiswasaparticularsuccessforthe Americanindustry. VivianeQuirkedrewparallelsbetweenthesystemsthatevolvedinFranceand Englandupto1965.ShesuggestedthatHenryDaleattheNationalInstituteofMedical ResearchandErnstFourneauatthePasteurInstituteexhibitedmanyparallelsbothcoming fromacademicbackgrounds,workinginthepharmaceuticalindustry,thenreturningto academia,butinvestingheavilyincollaborativeresearch.Shearguedthatcollaborative workdevelopedwidelyinFranceintheinterwarperioddespitealackofsupport,whereas
34 itdevelopedinBritainasaresultofgovernmentsupportandlargelythroughDale.
RobsondescribedtheBritishdrugindustryascomprisingfourdistincttypesoffirm
35 attheendofthenineteenthcentury :
1.
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).
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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andDavenportHinesandSlinn(Glaxo)andalthoughadefinitivehistoryofBurroughs Wellcomeisawaited,mostattentionhasfocussedonphysiologicalstandardisationby
36 TanseyasBurroughsWellcomeproducedvaccinesandantitoxinsfrom 1895.
economicsoftheBritishpharmaceuticalindustrywithFranceandSwitzerlandbutagain
38 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.
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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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:hestatedthatParke
39 DavisdidnotformallyestablishaChemistrydepartmentuntilthe1920s.
KarlH.Beyer,Discovery,DevelopmentandDeliveryofNewDrugs(NewYork:S.P. MedicalandScientificBooks,1978):43.
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
25
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.
40
41
JohnP.Swann,(1988):356. M.Robson,(1988):82105.
25
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
26
Iteventuallytookamassiveinternationalefforttodeveloppenicillinandthiswasonly stimulatedbythewartimeneedsandfollowingthesuccessofthesulphonamides.Nonew drugisusefulunlessitcanbemanufacturedreliablyandpartofthechallengeforBritainin thisinterwarperiodwastoencouragethetrainingofchemicalengineersandmanufacturing chemiststomakethispossible. However,detailsasideQuirkeprovidesavaluablecomparisonofBritainandFrance, inwhichshecontraststhecentralcoordinatingrolesofthePasteurInstituteandtheMRC forwhichsheidentifiedtheimportantroleofDaleinbreakingdownthebarriersbetween industryandacademia,thoughasIwillshowbarriersstillexistedtogettingclinicaltrials performed. 1.3ClinicalTestingofNovelDrugs. Stilllessattentionhasbeengiventotheoriginsofclinicaltrialsofnewdrugsfrom industry.Someauthorshavechartedancienttrialsorthedevelopmentofmeasurement
42 inmedicine. Thehistoriographysuggeststhatnumericalmethodsofassessmentin
medicinespreadfrom ParisatthestartofthenineteenthcenturyandTroehlerexamined
43 thisinathesis,whichfocussedonthetechniquesandthescopeofdatacollected. His
26
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
27
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 AbrahamFlexners1910reportIwilldescribeparallelstothesystemdevelopedbythe
44 MRCinBritain. HarryMarksexaminedtheestablishmentofcooperativeclinicaltrialsin
America,emphasisingthatotherformsoftherapeutictrialspredatedrandomised
45 controlledtrials. Heexaminedhowtherapeuticdecisionsweremadeandemphasisedthe
44
AbrahamFlexner,MedicalEducationintheUnitedStatesandCanada(NewYork: CarnegieFoundation,1910).
45
27
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
28
manycentressothattherewasnotanundueinfluenceofoneortwophysiciansineach centre.Heexaminedthemajorchemotherapeuticagents,includingSalvarsan, sulphonamidesandpenicillinandconcludedwithsomelaterworkonoralhypoglycaemic drugs,buthedidnotexaminehowindustrygottheirdrugstested.LikeQuirke,Iconclude thatthesysteminBritainwasmorecentrallycoordinatedbytheMRC,thanthe independentsystemofcollaborationsthatexistedinAmerica. InBritain,even afterBurroughsWellcomedemonstratedphysiologicalactivityof theirdrugs,testedthemforpurityandstandardisedthemintheirownlaboratories,theystill haddifficultyinestablishingclinicaltrials.WhereasinGermanytheclosecollaborations betweenfirmsandpharmacologistsledtoearlytestingofnewproductsinclinicaltrials,it wasdifficulttomakethesearrangementsinothercountries.GeraldGeisondescribedthisin
46 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
28
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
29
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:theModelofInsulin (1989):169.
49
C.C.Booth,ClinicalResearchinJ.Austoker,L.Bryder(eds.)Historical PerspectivesontheRoleoftheMRC.(Oxford:OxfordUniversityPress,1989):205241.
29
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
30
modifythedoseordurationoftreatmentoreventosubstituteonedrugforabetter alternative,asindeedEhrlichdidwithneosalvarsan.
50 Quirke defendedtheprogressofBritishindustryindevelopingacollaborative
networkthroughtheworkoninsulin butitwasnotdifficultfortheMRCtofinddoctors readytotestinsulin,afterithadalreadybeenshowninCanadaandtheUSAto dramaticallylowerbloodglucose.ItwasquiteanotherthingforaBritishfirmtotesta novelchemicalinmanforthefirsttime.ThemorethatIlookedatthisproblem,themore surprisedIwasthatithadbeenignored.Itseemedtomethattheresearchtodatehadbeen fittedaroundthebestavailablesourcematerialratherthanconsideringthisfundamental question. DesireCoxMaksimovdescribedtheTherapeuticTrialsCommittee(TTC)asthe modelthatemergedfromtheearlierChemotherapyCommitteeforrandomisedcontrolled
51 trials. Herstudywascarriedoutinparallelwithmyownresearchandcoversmyperiod
Thus,herapproachwasverydifferent,ignoringtheproductsarisingfrom pharmaceuticalindustryresearchandconcentratingonthemethodologyofthelargertrials
54 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..
30
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
31
55 arisingfromacademicresearch ratherthanadrugfromindustryandthepatulinstudies
wereusedtodescribethemechanisationoftrialsandthekeyroleofthestatistician,Major
56 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 afirst
55
L.Hogben,MajorGreenwoodBiographicalMemoirsofFellowsoftheRoyalSociety 7(1950):13954.
31
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
32
handsource,herinterpretationconflictswiththeaccountrecalledtomebySirAustin BradfordHill,thefounderoftherandomisedcontrolledtrialandbyhissurviving
57 colleagues. Therewerequitedifferentobjectivesandalsoethicalconstraintsin
thoughsherecognisedtherewasnodocumentaryevidenceandIfoundlittleeitherthefirst
61 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.
BradfordHillwasonlyappointedtotheTTCforthetenthandfinalmeetingin1939: TTCMinutes10,(28March1939),MRCFile1523/15(TTC).
32
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
33
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.CoxMaksimov,(1997):21. D.CoxMaksimov,(1997):21.
33
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
34
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
34
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
35
66 theideaofGovernmentshapingindustryhastakenroot. Amajoremphasisisplacedon
67 theroleofsignificantindividuals,andparticularlyFrancisCarr.
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
W.M.Gardner,TheBritishCoalTarIndustry,ItsOrigin,DevelopmentandDecline (London:Williams&Norgate,1915).
35
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
36
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
36
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
37
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,companiesbegantoemploytheirownpharmacistsand
69 physicianstoestablishtheclinicaltestingofdrugs, andthistrendevenbeganinthelate
1930s. Despitethebroadchronologyofthethesis,inevitablytherearesomeslightoverlaps betweensections.ForexampleitseemedsensibletoincludealloftheWaractivities, includingproductionandtestingofSalvarsaninonechapter,soIalsoincludedthework thatcontinuedonSalvarsanafter1918asitinvolvedthesameindividuals. FollowingonfromthisIntroduction,Chapter2describesthevariedoriginsofthe Pharmaceuticalindustryin thenineteenthcenturyandassessesthepositionofthesmall Britishcompaniesinrelationtotheirlargerinternationalrivals,contrastingtheethical manufacturerswithproducersofpatentmedicines.
69
37
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
38
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
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ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
39
Chapter7examinesthestrategyofBurroughsWellcomepostwarandespeciallythe period1925to1931,uptotheestablishmentoftheTherapeuticTrialsCommitteethrough thestrategicdebateswithintheirScientificandTechnicalCommittee. Chapter8examinestheactualworkingsoftheTherapeuticTrialsCommittee,how theyinitiallyfavouredBritishdrugsandhowthestudiescomplementedtheirownresearch andinterests.Thisexaminationofallofthedrugstestedgivesaninsightintotheresearch strategiesof British(andsomeforeign)firmsandallowsanassessmentofthesuccessor otherwiseoftheTTCgivinginsightsintothetesting,bothfromtheMRCperspectiveand thatofBurroughsWellcome(fromSTCMinutes19311939)andotherfirms. Chapter9offerssomeconclusions,bothbyreviewingthekeytopicsidentifiedandby comparingthepositionofBritishmanufacturersattheoutbreakoftheSecondWorldWar withthepositionthattheyfoundthemselvesinattheoutbreakofWarinAugust1914. Someopportunitiesforfurtherworkarethenidentified. Afullbibliographyofsourcesisgivenattheend.
39
TheOriginsofthePharmaceuticalIndustry
40
CHAPTERTWO:TheOriginsofthePharmaceuticalIndustry.
2.1TheGrowthofthePharmaceuticalIndustryintheNineteenthCentury. Earlynineteenthcenturydrugtherapywasaimedatalleviatingsymptomssuchas
1 feverandpain. By1900twoparallelbutoverlappingsystemsofdrugmarketinghad
evolvedinallofthemainmanufacturingcountries.Patentmedicineshadbeenavailable
2 forovertwocenturies,buttheiruseexpandeddramaticallyduringthenineteenthcentury.
Theywerepreparationswhoseingredientswerekeptsecret,andwhichweresoldunder
3 brandnamesforawiderangeofillnesses. Theirsuccessdependeduponheavy
40
TheOriginsofthePharmaceuticalIndustry
41
MorsonsandHowardssoldquininesulphateinsteadofcinchonafrom1821,andfirms wereabletocomparethebestsourcesofquinine.From1827firmssuchasMercksold
8 purifiedmorphine,insteadofopium,asdidT.H.SmithinEdinburghby1837. Firms
manufacturedplantextractsandinorganicremediesaccordingtothedemandsof
9 physicians. Inotherwords,doctorsdecidedwhichdrugswereneededandpharmaceutical
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).
6
7
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.
41
TheOriginsofthePharmaceuticalIndustry
42
Thepurityofdrugsproducedbyreputablefirmsimprovedastheirpharmacistsadopteda
10 moreprofessionalrole.
JacobBellofJohnBell&Co.wasoneofthefoundersofThePharmaceutical
11 SocietyofBritainin1841andwasPresident18569. WilliamAllenofAllen&
nineteenthcentury,theBritishpharmaceuticalindustrywasstrugglingtokeepupwithits
15 counterpartsinGermanyandinAmerica. Pharmaceuticalsevolvedonalargescalein
10
42
TheOriginsofthePharmaceuticalIndustry
43
industryadaptedandmadeuseoflaboratoryscienceasameansofdevelopingand
16 marketingcompetitivenewproductsinthe1880s.
Philadelphiabasedfirmscreatedandeffectivelycontrolledalucrativenewsector
18 ofthepharmaceuticalmarket,ethicaldrugssoldsolelytomedicalprofessionals. The
J.F.Marion,TheFineOldHouse:Smith,KlineCorporation'sFirst150Years (Philadelphia:SmithKline,1980).
19
43
TheOriginsofthePharmaceuticalIndustry
44
toreceivepecuniarycompensationorpatronageforsendingprescriptionsto 21 anyapothecaryshallbedisqualifiedfrombecomingamember.
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.
44
TheOriginsofthePharmaceuticalIndustry
45
26 terminologysuchas'dialysed'iron. TheymetareadymarketamongAmericandoctors
whowishedtominimisethepracticeofselfprescribingbypatients.OtherUSfirmswith rootsinpharmacyincludedA.P.Sharp,foundedin1827inBaltimore,thefirstinAmerica
27 toproducealkaloids. CharlesErhardtandCharlesPfizerestablishedtheirfirmin
28 Brooklyn,NewYorkbetween18458afterPfizerhadbeenapprenticedtoanapothecary.
HarveyC.ParkeandGeorgeS.DavisformedParkeDavisasasmallmanufacturing businessinDetroitin1866,andW.E.UpjohnfoundedTheUpjohnPillandGranule
29 CompanyinKalamazooin1886toproducefriablepills.
TheprincipaladvancesbyAmericanfirmswereincreatingnoveldosageforms suchassugarcoatedpills,whichwereconvenienttocarry,andsugarmaskedanybitter
30 tastes. Large scalemanufactureofpillsdevelopedfrom1857,andelixirs(solubleliquid
31 forms)from1859. Wyethpreparedcompressedhypodermictablets,andtablettriturates
werefirstmadein1861.Thesecouldbereadilydissolvedforinjectionorfortakingas
32 solutions. Thefirstmouldedmedicinesandcompressedpillsweremanufacturedin 33 Philadelphiain1863andtabletsweremadecommerciallyfrom1869. Wyethemployees
designedandpatentedthefirstrotarytabletpressinAmericain1872toproduceopiates, digitalis,strophanthusandquininetablets.By1876patentsweresecuredontheprocess
26 27
28
J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8. J.T.Mahoney,Merck&Co.(1959):2012.
C.Gunn,AHistoryofSomePharmaceuticalFormulationsinF.N.L.Poynter (ed.),(1965):13150.
31
J.T.Mahoney,Philadelphia:CradleofPharmacy:SmithKline&French,Wyeth andOthers(1959):312.
33
45
TheOriginsofthePharmaceuticalIndustry
46
34 andthemethodofcompressionofpills. Incontrast,Britainspillsweremadebyhand
untilAllen&HanburysboughttheirfirstpillmakingmachineatthePharmaceutical exhibitioninPhiladelphiain1876,buteventhennotabletswerebeingmadecommercially
35 inBritain. JohnWyethstated:Priorto1877theformula's(sic)thatweresoldintablet
formwereveryfew.Theyconsistedofsimplechemicalssuchaspotassiumchlorate,
36 ammoniumchlorideetc.andafter1877combinationsfollowed. Wyethalsostated:we
doclaimandweknowthatthepreparationswemanufactureareunsurpassedbyanyinthe
37 38 world. ParkeDavisformulatedsomeproductswithingelatinecapsulesfrom1887.
Dr.AbbottofChicagoprepareddosimetricgranules,atypeofpillwithaccurately
39 calibrateddoses,from1888.
Upto1880firmssuchasG.D.SearleofChicagoofferedhundredsofelixirs, syrups,powderedextractsandtinctures.SmithKline&Frenchhadacatalogueofabout
40 15,000items. Howevertheincorporationofexistingproducts,astabletsrequiredspecial
34
J.T.Mahoney,G.D.Searle(1959):14455J.F.Marion,(1980):103.
46
TheOriginsofthePharmaceuticalIndustry
47
41 conditionsofpreparation. An1884pricelistofEliLillyCo.ofIndianapolisstated:
SmithKline&Frenchanalysedeverythingmadeandorganisedaresearchlaboratoryin
43 1900andaphysiologylaboratoryfrom1911.
standardisedproductscouldbedifferentiatedonstrengthandpurity,reliabilityand consistency,ratherthanhavingtocompetelargelyonpricewithmanyfirmsproducingthe
45 samedrugs.
universitiessuchasWisconsin,whereinfluentialclinicianssuchasJohnJ.Abeloffered
41
43
44 45
46
47
TheOriginsofthePharmaceuticalIndustry
48
47 advice. SomeUSfirmssuchasAmericanCyanamidhadoriginsinchemical
53 &Co.wasfoundedatHoechst,nearFrankfurt. TheFarbwerkeFriedrichBayerwas
47
J.J.Beer,CoalTarDyeManufacturersandtheOriginsoftheModernResearch LaboratoryIsis49(1958):12331.
50
FromMercksAngelPharmacytotheWorldwideMerckGroup16681968 (Darmstadt:Merck,1968).
51
48
TheOriginsofthePharmaceuticalIndustry
49
Chloralhydrate,discoveredbyLiebigin1832wasextractedandtestedclinicallyas ananaestheticin1869,andthediscoveryofetherandphenolphthaleinin1871gavefurther
57 earlyindicationsofthepotentialbenefitsofsyntheticdrugs. PasteurandListershowed
thatphenolhadantisepticpropertiesandthisstimulatedGermandyefirmstodevelop furthersyntheticdrugsfromphenol,whichwasamajorwasteproductofthedye
58 industry.
ServicetoMan:MilestonesoftheHoechstPharmaceuticalCompanyFortschr.Med.102 .20(24May1984):7577.
54
E.Bumler,PaulEhrlich:ScientistforLife(NewYork:Holmes&Meier,1984):
80.
56
58
49
TheOriginsofthePharmaceuticalIndustry
50
59 UniversityofGttingen,andAGFAhadsimilarlinksinHeidelberg. Meister,Lucius&
BrningcollaboratedwiththeMarburgtrainedpharmacologist,HermannKolbeinLeipzig in18734,resultinginsyntheticacetylsalicylicacid,usedfortreatingrheumatismin1875
60 andasanantipyreticin1876.
By1878,Germanfirmsheldover60%oftheworlddyemarketandtheir dominanceinmanufacturingcapacityandproductionofchemicalintermediatesallowed
61 themtotakeanearlyadvantageintheproductionofsyntheticdrugs. Thus,thechief
industrialisednation(Britain)andthemostpracticalpeopleintheworldhadbeenbeaten
62 intheendeavourtoturntoprofitableaccountthecoaltartheypossessed.
andchemicalintermediatesthatwereessentialfordrugsynthesis:sulphuricacid,chlorine,
64 causticsoda,benzole,toluole,naphthalene,phenolandanthracene. Theysubdivided 65 plants,standardisedoutputsandindustrialisedtheprocessofinvention. Thenewhealth
59
T.Lenoir,AMagicBullet:ResearchforProfitandtheGrowthofKnowledgein GermanyAround1900:Minerva26(1988):6688.
60
G.MullerThurow,IndustrialisationofInvention:aCaseStudyfromtheGerman ChemicalIndustryIsis73(1982):36368.
62
E.W.Jenkins,FromArmstrongtoNuffield.StudiesinTwentiethCenturyScience EducationinEnglandandWales(JohnMurray:London,1979):8.
63 64 65
J.C.OgilvieWill,OnSalicylicAcidLancet(18December1875):87072. ThisappliedespeciallytoBadischeandHoechst:L.F.Haber,(1958):16,130.
50
TheOriginsofthePharmaceuticalIndustry
51
66 insurancelegislationin1883directeddyefirmsfurthertowardspharmaceuticals. Inthe
1880sand1890sMeister,Lucius&BrningandtheBadischeAnilinundSodaFabrik
67 (BASF)competedfortheadviceofthepharmacologistAdolphvonBaeyer andhis
Asecondstrategywastoemploytheacademicdiscoverer.In1883Meister,Lucius &BrninghiredAugustLaubenheimer,ProfessorofChemistryatGiessenUniversityand
69 heremainedwiththefirmuntilhisdeathin1904. PaulEhrlichinFrankfurtcollaborated 70 withLaubenheimerfrom1885. In1884BayersecuredCarlDuisberg,whohadtrained
inGttingenandJena,andheldaparttimepostwithvonBaeyer,tosetupapharmacology laboratoryatElberfeldatatimewhenonly40%ofGermanuniversities,andfew
71 elsewherehadsuchadepartment. Meister,Lucius&Brningdevelopedtheir
pharmaceuticaldepartmentafterLudwigKnorr,aformerstudentofEmilFischerat Erlangenwaspersuadedtojointhemin1893,andestablishedthefirstfulltimelaboratory
66
WalterSneader,(1985):29,84,114,250.
68
E.Bumler,(1984):xii,43,11012.
51
TheOriginsofthePharmaceuticalIndustry
52
whohadgainedexperiencewithEnglishdyefirmstoreturntoGermanyandestablish
75 laboratoriesatBayer(1888),Meister,Lucius&Brning(1891)andBASF. Asaresult
76 77 ofthefocusonpharmaceuticals,Meister,Lucius&Brning, Kalle, andMerckprepared
78 furthersyntheticantipyretics,antisepticsandpainkillers.
AfterthePasteurInstitutewasestablishedinParisin1888,theKochInstituteof HygieneandInfectiousDiseaseswasestablishedinBerlinin1890:bothhadstrong
79 supportfromtheirrespectiveGovernments. IncontrasttheBritishInstituteof
PreventativeMedicine(ListerInstitute)receivedlittlesupportfromtheGovernment,the
80 BritishMedicalAssociationorindustrialists. Koch'sInstituteattractedtheattentionof 81 manyGermanpharmaceuticalfirms. OneofKoch'sassistantswasplacedinchargeof
72 73 74
M.R.Fox,(1987):1718,20,23,989,111,126forCaro,and4,10,15,20,28,63, 66,70,945,106,114,141forHoffmann.
75
WiedieErstenHeilmittelnachHoechstKamenDokumentesHoechsterArchiven 8(Frankfurt:Hoechst,1965):8,15.
77
WalterSneader,(1985):86.
78
E.Bumler,(1984):49 50.
52
TheOriginsofthePharmaceuticalIndustry
53
82 thetuberculinproductionplantatMeister,Lucius&Brningin1891. WhenEhrlich
movedtoBerlin,hisongoingcollaborationwithMeister,Lucius&Brningplacedthemin apositiontotestbiologicalagentssuchasdiphtheriaandtetanusantitoxins,discovered
83 therebyEmilBehring.
derivativesofmorphinewiththeAustrian,JosefvonMeringandintroducedDionin,the
85 ethyletherofmorphinein1898.
Germanfirmsadoptedahardsellingapproach,discountingtheirdrugsand promotingthemheavily,astheyhadwithdyestuffs,establishingpricingandquota
86 agreements. Aspirin,discoveredbyBayerwaspromotedfrom1899onanunprecedented
82
WalterSneader,TheDiscoveryofHeroinTheLancet352(21November1998): 169799.
85
J.VonMering,PhysiologicalandTherapeuticInvestigationsontheActionof SomeMorphiaDerivativesTheMerckReport7(1898):513.
86
53
TheOriginsofthePharmaceuticalIndustry
54
87 scaleto30,000doctors. Toassisttheuptakeofthesecomplexnewdrugs,theyreplaced
CassellaconcludedasimilaragreementwithEhrlichinwhichhecededallproductsfor
91 themtoselluniquelyinreturnfor30%ofprofits.
87
C.D.Leake,(1975):157,1667C.C.Mann,M.L.Plummer,(1991):2331.
WalterSneader,(1985):55,98C.C.Mann,M.L.Plummer,(1991):2331J.J. Beer,(1959):366C.D.Leake,(1975):1667T.Lenoir,(1988):6688.
91
E.Bumler,(1984):125.
54
TheOriginsofthePharmaceuticalIndustry
55
Thusbytheturnofthecentury,Germanfirmshaddevelopedanefficientmeansof transformingwasteproductsofthedyeindustryintoextremelyprofitablenewlinesof drugs.Theyheldamonopolyintheproductionofchemicalintermediatesandcreateda scientificauraaroundtheproductsbycollaboratingclosely,andevenemployingwell knownpharmacologists.Theyextendedsalestechniquestoprovidefreesamplesto doctorsandperformedclinicaltrials,buttheyalsocontinuedtousetheiroldtechniques ofcartelsandpricefixingandpatentprotectiontocreatemonopolies,whichweredifficult tochallenge. In1899BritainwasfeelingthefullforceofGermanmarketing.N.H.Martinofthe NewcastlebranchoftheSocietyfortheChemicalIndustrywrote: Hardlyamonthpassesbutsomenewsubstitutioncompoundwithatrivial nametoindicateitsallegedmedicinalpropertiesandascientificnameto suggestprofoundresearch.Theycomewithlaboratoryandmedicinalreports 92 inalanguagecalculatedtodeceive.
SuchwastheflowofGermansyntheticdrugsthatacartoonintheNationalDruggiststated afewofthelatestspecimensoftheincreasingflowofforeignsyntheticsandasked,
93 Willtheyneverstop?
55
TheOriginsofthePharmaceuticalIndustry
56
94 preparemanynewchemicals. Herecommendedto:examineallpreparationswhose
Whenpharmaceuticalmanufacturersfirstpreparedbiologicalsera,itwasEhrlich whoarguedthatitwasessentialtouseseraofpreciselydeterminedconcentrationandhe
96 providedthisserviceforthem. Ehrlichrelatedchemicalstructuretoactivity:
Thisstructureactivitybasedchemicalapproachtodrugselectionfordevelopmentwas uniquetoGermany,eventhoughsomeBritishacademicsusedthisapproachonasmall
98 scaletostudypharmacologicaleffects. However,thisrationaltherapeuticapproachstill
leftproblems.CarlBrowningperformedresearchwithEhrlich andcontinuedtoexamine
99 acridineandtheneutralnonmethylatedproflavinewhenhereturnedtoBritain. Ehrlich 100 andhiscolleagueLudwigBenda examinedhundredsofacridinedyesontrypanosomes,
94
TheVereingteChemischeWerkeofCharlottenburgmarketedamodifiedversionof arseniousacid,Atoxyl:E.Bumler,(1984):109,187,249.
95 96 97
98
A.CrumBrown,T.R.Fraser,OnthePhysiologicalActionoftheSaltsofthe AmmoniumBasesDerivedfromStrichnia,Brucia,Thebeia,Codeia,MorphiaandNicotia Trans.Roy.Soc.Edin.25(1868):151 204D.B.Dott,R.Stockman,TheChemistry andPharmacologyofMorphineanditsDerivativesYearBookofPharmacy (London: Churchill,1888)34955J.M.FortescueBrickdale,RecentAdvancesintheRelation BetweenChemicalStructureandPharmacologicalActionBritishMedicalJournal (16 January1915):106W.D.M. Paton,TheEarlyDaysofPharmacologywithSpecial ReferencetotheNineteenthCenturyin ChemistryintheServiceofMedicine(London: Pitman,1963):789.
99
E.Bumler,(1984):1426,171,192,216,229.
56
TheOriginsofthePharmaceuticalIndustry
57
whichwereparasitesthatcausedsleepingsicknessintropicalcountrieswhereGermany
101 hadcolonialaspirations,andherelatedtheiractivitytotheirchemicalstructure. Alfred 102 Bertheim, DirectorofMeister,Lucius&Brningturnedthewholestaffontopreparatory
workforEhrlich,andBendaeventuallyjoinedtheirpartnerCassella,beforethefirms
103 mergedtoformHoechst. Optochin,(ethylhydroxycuppreine),aderivativeofquinine,
andTrypaflavin(acriflavine)werefoundtobeactiveinanimals,butneitherwassuccessful
104 inhumansandtheformerwastoxic. Thisraisedthequestionthatalthoughanimals
ThecontinuedsupportfromBayer,HoechstandtheVereinigteChemicalCompany
107 wasessentialtoEhrlich. HisworkontheantisyphiliticSalvarsanhighlightsthe
101
E.Bumler,(1984):1213,142,144,147,161,1656,171,192,204,2167,244.
57
TheOriginsofthePharmaceuticalIndustry
58
Hoechstsupplied60,000freesamplestodoctorstotreat10,000patients,andyetEhrlich wasstillcriticisedinsomequartersforintroducingSalvarsantooearly,andbyothersfor
111 delayingtheintroduction. By1911Hoechst'spharmaceuticalbusinessaccountedfor
58
TheOriginsofthePharmaceuticalIndustry
59
developmentofatreatmentwithcompletelyharmlesssubstanceswouldremainan
115 unfulfilleddream. Thus,Ehrlichcanbeseendevelopinganimalmodelsofinfection,
59
TheOriginsofthePharmaceuticalIndustry
60
1901,ofwhich69%werePh.D.s,10%hadaTechnicalDiplomaandafurther5%had both.ThiscomparedwithlessthanhalfofthetotalinEngland,whereonly21%wereeven
119 graduatesandonly10%hadaDiploma. Bayer'sstaffdoubledeveryfiveyearsfrom
119in1875to5,000inMay1902,including160chemistsand260engineersplus680 clerks.By1913theyhadgrownto10,600.Badischehad2,500menandHoechsthad
120 1,600including54chemists. Attheendof1913Hoechstemployed8,100includinga
121 commercialandscientificstaffof871andCassellaemployed3,000menby1913.
116 117
W.Bernsmann,(1967):7681.
C.Duisberg,TheEducationofChemistsChemist&Druggist48(13June1896): 83132.
118
R.Meldola,TheScientificDevelopmentoftheCoalTarIndustryinW.M. Gardner,(1915):136.
121
L.F.Haber,(1971):128.
60
TheOriginsofthePharmaceuticalIndustry
61
123 timeshigherthanBritishpharmaceuticalfirmsbutalsowereincreasingatafasterrate.
DuisbergofBayerwantedpharmaceuticalmanufacturerstomerge,butinsteadtheyformed theinformalPharmaIGin1905,withMerck,Gehe,J.D.Riedel,KnollandC.F.
127 Boehringer. TheonlyimportantpharmaceuticalfirmoutsideofthePharmaIGwas
ScheringanditssubsidiaryC.A.F.Kahlbaum.PharmaIGfirmsagreedtopoolprocesses,
122
L.F.Haber,(1971):133.
123
T.I.Williams(ed.),AHistoryofTechnology:TwentiethCentury190050volume V1(Oxford:ClarendonPress,1978):479.
124
SirWilliamA.Tilden,TheSupplyofChemicalstoBritainandherDependencies inW.M.Gardner,(1915):325.
125
61
TheOriginsofthePharmaceuticalIndustry
62
andexperienceandupholdeachotherspatentsandkeptcloserelationswiththedyefirms.
128 BayerandMerckalsocametoanagreementconcerningproductionofsedatives. British
firmsreliedonparticipatinginGermanruncartelstogivethemaccesstoatleastsome
129 modernGermandrugs. ManyofthesearedetailedinSlinnsaccountofMay&Baker 130 andincludedcartelsforcamphor,bismuth,chloroformandmercurialpreparations.
OutputofGermandyefirmstrebledfrom1881to1900,andtheirmarketsharerosefrom 50%tobetween8090%.By1914theGermanfirmsrepresentedanoverwhelming
131 dominantforce.
AbriefmentionhowevermustbegivenaboutSwissfirms,whichoperatedasifan extensionoftheGermanindustry.SeveralSwissfirmssituatedaroundBaselevolvedfrom
132 dyemanufacturersinasimilarwaytoGermanfirms. TheGesellschaftfrChemische
andunlikeotherSwissfirmsdidnothavedyestuffsroots.Inordertogainpatent
134 protectionitsoriginalsitewaswithinGermany. ThefiveSwissfirmscentredinBasel
128 129
L.F.Haber,(1971):134.
JudySlinn,(1984):80.
131
62
TheOriginsofthePharmaceuticalIndustry
63
(CIBA,Sandoz,J.R.Geigy,L.Durand,Huguenin,andtheBaslerChemischeFabrik)
135 employed1,326peoplein1901andoperatedprofitsharingpoolsbetweenthem.
CIBAhad1,600staffin1913,HoffmanlaRochehad550,Geigy400,Sandoz340and DurandandHuguenin100.CIBAbeganmanufacturingpharmaceuticalsintheearly
136 1900'sandsoonaseparatesectionwascreated. Switzerlandthushadastrongindustry,
butwasstillheavilydependentonGermanyandboughtalltheprocesschemicalsandupto
137 80%ofallintermediatesfromGermany.
135 136
L.F.Haber,(1971):20,113and169,F.A.SherwoodTaylor,(1957):384.
L.F.Haber,(1971):19,163.
125.
63
TheOriginsofthePharmaceuticalIndustry
64
localfirmswithpharmacyrootshavelongsincedisappeared,butsomedidwellsuchas JamesWoolleySons&Co.,Manchester(founded1796),ThomasKerfoot,Ashtonunder
141 Lyne,(1797),ArthurCox &Co.inBrighton(1839) ,StaffordAllen&Co.London, 142 143 (1833) andWilliamRansom&Sons,Hitchin(1846). Thefinechemical
firmestablishedinWoodStreetinLondonin1828byJohnSidneyLescher,afounderof
147 thePharmaceuticalSocietyandJohnEvans. May &BakerfoundedinBatterseain
1834,producedbismuth,mercurials,etherandspiritsbutmostnoveldrugswereboughtin underlicense.TheypreparedphenacetinandSulphonalunderan1887contractwith
148 Bayer. By1900May&Bakeremployedabout100people.From1903they
141
S. Miall,(1931):133.
L.G.Matthews,(1962):227,2312S. Miall,(1931):133.
64
TheOriginsofthePharmaceuticalIndustry
65
DuncanFlockhardt,foundedin1806inEdinburgh,producednitrousoxideandthen
150 chloroformanaestheticsfrom1848andJ.F.MacFarlan wasfoundedin1864. T.H.
manufacturer,anddidnotproduceethicalpharmaceuticalsuntilaftertheSecondWorld
152 War. In1851thepatentmedicinemarkethadaturnoverof250,000andthelargest
companywasThomasHollowayofLondon,whointhatyearproduced25,000worthof
153 pills. T.&J.Smith(laterSmith&Nephew,whenH.N.Smithjoinedin1896)was 154 establishedinHullin1856,butremainedsmalluntiltheWar. A.BoakeRobertswas 155 foundedin1865initiallyproducedbrewingchemicals,flavouringsandessentialoils.
GlaxohadoriginsinNewZealandasJ.Nathan&Co.,importingdairyproduceinto Britainandonlybecameestablishedasababyfoodmanufactureratthestartofthe
156 157 twentiethcentury. TheLondonDrugCompany,andTaylors concentratedonthe
retailtraderatherthanproducingtheirowndrugs.Boots,establishedin1877were
158 retailersandexpandedtoachainof200shopsbytheendofthenineteenthcentury.
150
T.A.B.Corley,TheBeechamGroupintheWorldsPharmaceuticalIndustry 191470GesellschaftfrUnternehmensgeschichte(1994)(1):1830.
153 154
PharmacyinScotlandChemist&Druggist(27July1912):146.
W.J.Bush,StaffordAllenandA.BoakeRobertsnolongerexistandweremerged aspartofagroupcalledInternationalFlavouringandFragrancesInc.,www.iff.co.us
156
GeoffreyTweedale,(1990):50,78,83.
65
TheOriginsofthePharmaceuticalIndustry
66
EventwoofthelargestBritishfirms,BurroughsWellcomeandAllen&Hanburys,
159 employedlessthan200staffinthe1890's. Allen&Hanburyswasfoundedin1715
Fordredwasemployedfrom1878,butformorecomplexteststheyturnedtothe
161 PharmaceuticalSociety. Theyemployedapharmaceuticalanalyst,WilliamRalphDodd
evaporationunits,rollers,electricmotorsandstills,andthechemistWilliamRadford,a trainedbuilder,eventuallybecameworksmanager.Between1900and1914,16,500was
159
160
161
GeoffreyTweedale,(1990):73,87,89,108,115.
C.Gunn,inF.N.L.Poynter,(1965).
66
TheOriginsofthePharmaceuticalIndustry
67
TheonlysignificantmergerinBritainwasofseveralsmallfirmsin1908toformBritish
166 DrugHouses. Theyproducedhighlypurifieddrugsandhadlaboratoriesforquality
control,advertisingthattheywerethefirsttoofferawarrantyofnotonlycompliancewith theU.S.FoodandDrugsActandBritishPharmacopoeiabutevenmorestringent
167 standards.
165
67
TheOriginsofthePharmaceuticalIndustry
68
Perkin,andheadofPerkins&Sons,whobecameheadofchemistryattheBorough
171 172 PolytechnicInstitutionin1897 RaphaelMeldola(18491915) whostudiedatthe
168
ForaseriesofarticlesonthisseeW.M.Gardner,(1915). M.R.Fox,(1987):100.
AlexanderFindlay,WilliamHobsonMills(eds.),BritishChemists(London:The ChemicalSociety,1947):96110.
173
68
TheOriginsofthePharmaceuticalIndustry
69
andwasthenworksmanageratClaytonAnilineuntil1901,whenfor2yearshewasa
174 consultant,thenProfessoroftinctorialchemistryatLeedsUniversity. TheseBritish
2.7.2TheLackofPracticallyTrainedBritishChemistsandChemicalEngineers. ChemistsinBritainwereinshortsupplyattheendofthenineteenthcentury,
178 especiallythosewithpracticalexperienceinpharmaceuticals. WhenWilliamPerkin
1851,untilhemovedtoSouthKensingtonin1856,withHenryRoscoetakingupthechair inManchester.AnotherwasthelaboratoryofTheophilusRedwood,Professorof
174
ChemicalEngineering (Washington:AmericanChemicalSociety,1980).
179
180
JournaloftheSocietyoftheChemicalIndustry (1885)4:437.
69
TheOriginsofthePharmaceuticalIndustry
70
ofeminentGermanchemistsincludingA.W.Hoffmannperformedresearchandtaughtat
183 theRoyalCollegeofChemistryfoundedin1845. Franklandworkedalongsidehim
sincetheopeningandsucceededHoffmannin1865,andheledtheearlycampaignsfor bettereducationofchemists.SouthKensingtonbecameanimportantsourceofindustrial
184 chemists. JustbeforeHoffmannleftforBerlin,HenryEdwardArmstrongjoinedthe
Germany,werebehindtheformationoftheSCIin1881,whichlobbiedforpatentreform
187 andtechnicalandpracticaltrainingofchemists.
182
TheophilusRedwood,ObituaryJournaloftheSocietyoftheChemicalIndustry 11(1892):2289.
183 184
D.S.LCardwell,(1972):867.
D.S.L.Cardwell,(1972):127132.
187
W.H.PerkininW.M.Gardner,(1915):1SirWilliamA.TildeninW.M. Gardner,(1915):332,377S.Miall,(1931):86:A.J.Levine,(1967).
70
TheOriginsofthePharmaceuticalIndustry
71
190 onchemicalengineeringin1901,basedonhisownlecturesinManchesterfrom1887.
tocompetewithforeigners,soundscientificeducationwasneededandhenotedthat
192 Americapromisedtobecomeamajorcompetitor.
T.H.HuxleywrotetoTheTimesin1886thatthelastyearsofthiscentury promisetoseeusembarkedinanindustrialwaroffarmoreseriousimportancethanthe
193 militarywarsofitsopeningyears. ThelimitedresourcesofBritishpharmaceutical
firmsweredescribedin1889:
188
F.W.Keeble,(1941):240. G.VanPraagh,(1973):56.
190
191
L.F.Haber,(1971):63. G.VanPraagh,(1933):52.
71
TheOriginsofthePharmaceuticalIndustry
72
Ourhistoricdrughouses,whohavealwaysactedmoreorlessas manufacturers,havemuchtotheirdetrimentneglectedresearch.Each establishmentshouldhaveitschemistengagedinthechemicalexamination ofnewremediesforthediscoveryofactiveprinciples,etc.whichmusthave tendedtohavekeptusoutofthearmsofforeignersformostofouralkaloids andotherorganicsubstancesnowinsuchincreasingdemandin 194 medicine. Giventhelackofchemicalengineers,itisimportanttointroduceonethattrainedwith HenryArmstrongandlaterenteredindustrywithBurroughsWellcomeandplayedamajor partinthedevelopmentofchemicalengineeringinthepharmaceuticalindustry. FrancisHowardCarr,astudentofArmstrongatFinsburybecameoneofthemost
195 importantchemicalengineersinthepharmaceuticalindustryintheinterwarperiod.
CarrexplainedthattherehadbeeninsufficienttrainedchemistsinBritain:
194
T.A.Henry,(1950):62 81.
72
TheOriginsofthePharmaceuticalIndustry
73
Itisnotsomuchmorecollegesandmorestudentsasitisbettermethods oftrainingwhichneedtobeconsideredinconnectionwiththe educationalquestionwhichisonlyoneofthemanyimportantsidesofthe problemofthechemicalindustryinthiscountry.Thetechnicalcollege shouldgobeyondtheprocessofdevelopingthemindtothatofthe 198 applicationofmentalprocessestotheproblemofindustry. CarrbecameactiveinpromotingpracticaltrainingofchemistsatFinsbury,buthealsohad asignificantdirecteffecthimselfintrainingothersonthejobashemovedfromfirmto firm. HejoinedBurroughsWellcomeatDartfordinJanuary1898asChiefManufacturing Chemist,andhisinfluencetherewillbediscussedinChapter3. 2.7.3.PatentProtection. SCImemberswerebehindchangesinthepatentlawswithIvanLevinsteinon
199 behalfofLevinsteinsandotherdyefirms,andThomasTyrerleadingthecampaigns.
andwhentheoriginalpartnershipwasdissolvedhehadsetuphisowncompanyin1898by
201 acquiringtheStratfordChemicalWorksinEastLondon.
197
F.H.CarrarchivesatImperialCollegeTranscriptsbyA.E.GuentherB.CARRFH
6.
198
F.H.Carr,PresscuttingsletterOpinionsonEducationPre1914,Carr2130 B/CARRIV.3
199
M.R.Fox,(1987):216.
JudySlinn,(1984):54.HewasawardedthemedaloftheSocietyoftheChemical Industryin1910andremaineditstreasurerforthe10yearsbeforehediedin1918.
73
TheOriginsofthePharmaceuticalIndustry
74
BromboroughontheRiverMersey,whileasecondgroupcomprisingmainlyHoechst
202 boughtasiteatEllesmerePort,Cheshire.
2.7.4AlcoholSuppliesandDuty Britishdyefirmshadcampaignedforlongperiodstohavetheexcisedutieson ethanolreduced.Alcoholwasneededasasolventinwhichtodissolvevariouschemicals inordertogetthemtoreact,andwasrequiredinthepreparationofsaltsandasachemical intermediateitselfinarelativelypurestate.Inadditionitwasessentialtohaveasupplyof cheapacetone,andaceticacid. However,thegovernmentbelievedthatifalcoholwerenot taxedheavily,itwouldbeusedfordrinkinganddistillationandinBritainspiritswere methylatedtopreventthis. Thegovernmentalsohadconcernsoverthehighamountsof alcoholusedinpatentmedicinesandtonics. However,boththeexcisedutyandthe purificationcostswereprohibitiveforindustry,andasaresultcertaindyesandchemicals couldnotbeproducedcosteffectivelyinBritain. Thegovernmentgavenoconcessionsto
204 industry incontrasttoGermanywhereitwasavailableatspecialratestoindustry. The
priceofetherwasthreefoldhigherinEnglandthaninGermany,althoughBritaindid
205 prohibittheexportofphenolfrom1901. Adepartmentalcommitteeonalcoholreported
onthesituationin1905,butdidlittletohelpasthegovernmentfailedtoreducethe
206 duty. Absolutealcoholwasespeciallyusedforthemanufactureofchloralhydrate,and 207 in1913weimported28,994proofgallonsfromGermany.
Theavailabilityofacheapsourceofmanufacturedalcoholasastartingmaterialfor drugproductionwasconstantlymentionedasoneofthemainhurdlestodrugdevelopment.
202 203 204 205 206
DepartmentalCommitteeonAlcoholReportQ1378,(ed.)2477(London:HMSO, 1905).
207
Chemist&Druggist85.2(19September1914):489M.R.Fox,(1987):43.
74
TheOriginsofthePharmaceuticalIndustry
75
AttheoutbreakofWaritwasstatedthattherewasfurtherdiscussiononalcoholsupplies
208 anditwasstatedthat: ifthiscountryhaddutyfreealcoholGermanywillnotbeina 209 positionforsometimeafterthewar,ifeveragaintoexporttheirpreparations.
totheperiodbeforethewar.HerecalledthatstatementstotheeffectthattheBritish chemicalindustrywasnegligiblewereexaggeratedasthenumberofworkersinthe
211 chemicalindustrieshaddoubledbetween1900and1914. Furthermoretheshortagesof
syntheticswere: Notsolelybecausetheywerenotmadehere,forseveralfirmshadachieved thatalreadybutantipyrin,aspirin,salicylicacid,phenacetin,chloralhydrate, salol,phenolphthalein,saccharin,veronal,sulphonal,trional,eucaineand novocainewerenotmanufacturedhereandtheseamountedtoover1m 212 worthofsyntheticdrugs. Thisapparentlymisleadingquotationmeantthatalthoughtechnicallymanyofthe chemicalscouldbemade,atleastonasmallscale,itwasnotpossibleforBritish manufacturerstopreparetheminbulkonacompetitivebasis.Owingtoourinferior organisationwethusbecameinameasuretheshuttlecockofGermanmenofbusiness. Itwasstated:beforethewaritwouldhavebeenverydifficulttoproducethesalicylates here.EvensimplesyntheticssuchastheunpatentedAspirinwerenotproduced
208 209
F.M.Perkin,inW.M.Gardner,(1915):298314.
EdwinJ.Tookey,MakingFineChemicalsChemist&Druggist85.1(29August 1914):63.
210
F.H.Carr,SyntheticOrganicDrugs:TheirManufactureasAffectedbytheWar Chemist&Druggist88.4(29July1916):778779.
75
TheOriginsofthePharmaceuticalIndustry
76
commerciallyinBritainbecauseitcouldnotbeproducedatpriceswhichcouldcompete
213 withthoseatwhichGermanywasabletoofferthem.
TheantifebrileeffectofAntipyrinhadbeendescribedandpatentedinJuly1883, buteventhoughallofthesyntheticpatentshadexpiredBritishfirmscouldnotprepareitto
214 sellcompetitivelyagainstGermanfirms,andthesamewastrueofLanolines. In
additionsomealkaloidsincludingatropine,cocaine,emetine,hyoscine,morphine, ergometrinewereonlymanufacturedinGermany.Carrcontinued: PreWarGermanystradewasverymuchenhancedbysellingcartelsand thedrawingtogetheroflargemanufacturingconcerns.Thefirst achievementsweretheeliminationofcompetitionwithinGermanyandthe organisationofconcertedeffectstoundersellrivalsinthoselineswhere dangerouscompetitionseemedlikelytoarise.Therewascertainlyplentyof evidenceofthesesalescartelsandthepracticeofsellingbelowcostatthe 215 leastthreatofcompetition. Insummary,aseriesoffactorsconspiredagainstBritishmanufacturingchemists.Firstly therewerelessuniversitytrainedchemistsinBritainthaninGermany,andmanyofthem weretrainedontheoreticalratherthanpracticalgrounds.ThesizeofGermanfirmswas muchgreaterthanBritishfirms,sothereweregreatereconomiesofscaleandGermany hadsubsidisedtransportandcheaperrawmaterials,particularlyethanol.Itwasnotbeyond thewitofBritishchemiststomakethedrugs,buttheycouldnotmanufacturethemas cheaplyastheGermanscould.However,althoughpriortothewar,themanufactureof organicfinechemicalproductsbysynthesiswastoaverylargeextentacontinental
216 monopolytherewasneverthelessabeginningmadewithinthiscountry.
Chemist&Druggist 85.2(15August1914):37patent26429from22July1883.
D.L.Howard,British&ColonialPharmacist(August1926):243.
76
TheOriginsofthePharmaceuticalIndustry
77
glaucomaamylnitritesforanginaandthediureticscaffeine,theobromine,diuretinand
217 urotropin. OutofatotalofchemicalimportsfromforeigncountriesandBritish 218 possessionsof1.3m,morethan25%wasfromGermanyin1913. Figures,specifically
forthesyntheticalandotherdrugs,whichhaveinsomewaysrevolutionisedmedical
220 science,andalsomanyofthemoreimportantdisinfectants. Germansyntheticswere 221 seenby1914asaseriouscompetitiontoourtrade.
217 218
VivisectionVindicatedBritishMedicalJournal (16March1912):6267.
WarandBusinessChemist&Druggist88.4(29July1916):7989.
220
Prof.W.H.Perkin,ThePositionoftheOrganicChemicalIndustryinW.M. Gardner,(1915):408.
221 222
S.Chapman,(1974):96.
MalayFineChemicalsChemist&Druggist85.1(22August1914):46D.B. Dott,VegetableAlkaloidsHowtheWarhasAffectedProductionChemist&Druggist
77
TheOriginsofthePharmaceuticalIndustry
78
2.9ConcludingRemarks. InthelatterhalfofthenineteenthcenturyBritainhadcometorelyonGermanyfor manydrugsandinparticularsyntheticdrugs.BritainexportedcoaltarstoGermanyand thenimportedfinisheddyesandasaresultfailedtodevelopitsdyeindustry,sobecoming reliantonGermanyforchemicalintermediates.Manyofthedrugswereneededurgently fortheWarpainkillers,anaestheticsandantisepticsplusantitoxinsandvaccines.The focusofBritishfirmswasmoretowardsextractionofoils,alkaloids,glucosides,thanthe preparationofsyntheticchemicals.Britishfirmsweresmallincomparisontotheir Germancounterpartsandcouldnotcompeteonefficiencyofproductionorprice,andif theytriedtotheGermanshadmanycartelsandpricingarrangementsthatitwasbestnotto competeheadtohead.Britishfirmsthereforeproduceddifferentalkaloidsandextracts. WhereasGermanyledthewayonsyntheticchemistry,itwasinAmericathatmostnovel dosingformswereinventedandthisbringsustoanexaminationofhowanAmerican importerofmedicinescreatedaniche,byestablishinghisownfirmofBurroughs Wellcome.Thesuccessofthisfirmanditsadoptionofchemicalsyntheticworkisthe subjectofthenextchapter.
78
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
79
CHAPTERTHREE: BurroughsWellcome:BritishOriginsofCollaborativeResearch. 3.1Introduction. InthischapterIexaminehowthefirstresearchbasedBritishpharmaceuticalfirm, BurroughsWellcome,restructuredthepharmaceuticalmarketinBritainbyincorporating novelalkaloidsandGermansyntheticdrugsintoAmericanstyletablets,andbytakingthe bestofbothcountriesmarketingtechniques:theuseofTradenamesandscientific advertisingfromGermany,andtheuseoftravellingrepresentativessellingdirectlyto doctorsasinAmerica.Withthecreationofscientificlaboratoriesemployingprominent physiologistsandchemists,BurroughsWellcomechangedtherelationshipsbetween industry,academiaandgovernmentinBritain,andbetweenlaboratoryscienceandmedical practice.BurroughsWellcomewasthefirstBritishfirmtorecognisethecommercial advantagesofadoptingscientificmethodsandbasingnewproductsonlaboratory investigationstheaimthroughoutwastodifferentiatetheirproductsfromthoseofother
1 firms. Whenthegovernmentthreatenedtaxingthemaspatentmedicineproducers,
becauseoftheiradvertisingandimportationofmedicinesfromAmerica,thefirm respondedbyproducingethicaldrugs,characterisedchemicallyandstandardisedby biologicaltestinginanimals. IwillshowhowBurroughsWellcomeutilisedsyntheticchemistryonasmallscale toconfirmthestructureofphysiologicallyactiveprinciplesisolatedfromplants,andhow theyinvestigatedtheactivityofsyntheticchemicalderivativestogainanunderstandingof therelationshipofchemicalstructuretophysiologicalfunction.Thishasnotbeen previouslyrecognisedasacharacteristicoftheBritishpharmaceuticalindustryattheendof thenineteenthcentury,anditwasthesechemicalskillsthatenabledthefirmtoeventually produceitsownsyntheticdrugs.EvenBurroughsWellcome,theBritishfirmwiththemost advancedchemistry,onlyrarelymanufacturedsyntheticdrugsonacommercialscale.In 1908FrancisCarrcitedthatproductionofsuprarenalhormonewasperformed chemically,whilecodeineandoutofpatentdrugssuchasAtoxylandisoquinoline
79
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
80
2 derivativesofadrenaline(Suprareninsynthetic)weremadeinsmallquantities. However,
BurroughsWellcomechosenottocompetedirectlywithGermanfirmsinproducing syntheticdrugstheysolddifferentalkaloids,incorporatedGermandrugsintotheirown uniqueTabloidsanddifferentiatedtheirproductsbypurifyingandstandardisingthemin animaltestsagainstpuresyntheticchemicalstandards.Indoingsotheycreateda frameworkforestablishinganewtypeofdrugdevelopmentinBritain. ThischapteralsointroducesthemanyindividualsfromBurroughsWellcomethat playedamajorroleintheestablishmentoflaboratoriesattheMRC,thePharmaceutical Societyandinotherpharmaceuticalfirms,andhelpedtodeveloptheregulatoryframework fordrugdevelopmentintheinterwarperiod. ThehistoriographyofthefirmofBurroughsWellcomehaspreviously concentrated
3 onthefirmspharmacyorigins. Tanseyhasexaminedtheoriginsofphysiologicalresearch
4 indetail. Othershavefocusedonthepartnersthemselves,particularlyWellcome,because 5 ofhislastinglegacy. Thechemistryandmanufacturingsidehasreceivedlittleattention,
D.L.Howard,British&ColonialPharmacist (August1926):243.
80
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
81
HereIshowthatthesituationwasmorecomplex.Iarguethatthechemistryperformedin Britainhaspreviouslybeenverymuchunderestimated:techniquesandexpertisedeveloped beforetheGreatWarexplainhowBurroughsWellcomewereabletorapidlyproduce syntheticdrugswhentheybecameunavailablefromGermany. 3.2TheEstablishmentofBurroughsWellcome(1880). InordertounderstandthestrategiesadoptedbyBurroughsWellcomeitisessential tounderstandthefirmsoriginsasanimporterofAmericanmedicines.Althoughseveral authorshaveexaminedpartsoftheBurroughsWellcomestorythereisnocomprehensive overview.ThefollowingaccountisbasedmostlyonprimarysourcesattheWellcome FoundationandshowsthatbothBurroughsandWellcomebuiltupontheircontactsin Philadelphia,LondonandCambridgetoestablishtheirfirm.SilasMainvilleBurroughs (18461895)hadworkedinpharmaciesinLockportandBuffaloinAmericabefore graduatingfromthePhiladelphiaCollegeofPharmacyin1877.Hehadanearlyinterestin
7 tabletsandhisthesiswasonTheCompressionofMedicinalPowders. Hefirstcameto
Britainin1878toestablishaLondonofficeforthePhiladelphiapharmacybasedethical
8 manufacturingfirmofJohnWyeth&Co. Burroughsinitiallyintendedtoonlyspend612
monthsinEngland,butseeinganopportunitytosellnoveltablets,hesetuphisown businessfromApril1878inGreatRussellStreet,London,assoleimportingagenton
9 behalfofWyeth. ThenoveltyoftheirdrugswasemphasisedinWyethsBritish
advertisements:Purity,activityandbeauty.Elegantpharmaceuticalpreparations,
10 compressedpowdersorpillsandmedicinalfluidextracts.
G.MacDonald,(1980):57,1921ObituaryofSilasBurroughsChemist& Druggist47(9&16February1895):213214,254258.
9
81
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
82
In1880BurroughsbegantoimportthesugarcoatedpillsofLanmanandKemp,afirm
12 basedinNewYorksince1858. Toconsolidatethisexpansion,Burroughsoffereda
partnershiptoHenryWellcome,whohadalsograduatedfromthePhiladelphiaCollegeof
13 Pharmacyin1874. WellcomehadbeenapharmacistwithPoole&Geisingerfrom1866
16 BurroughsWellcomeCo.wasfoundedon25September1880. InOctober1880
thefirmexpandedintotheadjacentsite,whichtheyusedasawarehouseandSudlow
11
Thisremainedtheheadquartersuntilburntdownfollowingbombdamageinthe SecondWorldWar.G.MacDonald,(1980):2430.
12
ArticlesofAgreement,WF88/47:8G.MacDonald,(1980):5.
82
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
83
17 becameGeneralManager. By1881BurroughsWellcomeimporteddrugsforseveral
18 firms. However,tensionsdevelopedbetweenBurroughsWellcomeandWyeth,because
oftheexpandingcollaborationswithotherfirms,issuesaboutqualityandpricing,and BurroughsexploitationofthenoveltyofWyethsproductsbyregisteringthetrademarks
19 oftheirethicaldrugsunderhisownname. JohnWyethfeltBurroughsalwayshadwhat
claimedthatBurroughstooktoomuchprofitinBritainandfailedtoreachsalestargets despitespendingtoomuchonadvertising,thoughasacounterargumentBurroughs complainedthattheroyaltyleviedbyWyethaddedtohisprices.JohnWyethfeltthatthey shouldobtainpremiumpricesbyemphasisingtheethicalnatureofhisproducts: Thereisnopossiblesimilaritywithpatentmedicines,hestressed:[We] gaveyoustandardpreparations,[including]ourcompressedpills... [which]...nooneelsecanmanufacture,atrade[which]onceestablished cannotbetakenfromyoucomparedwithproprietarymedicines,which 21 requirecontinuedadvertising. WyetharguedthattheirethicalvalueswerecompromisedwhenBurroughssoldsub
22 standardversionsofWyethsBeef,WineandIron. OntheotherhandWyethprepared
somedrugstothestandardsoftheAmericanratherthantheBritishPharmacopoeia,due
17
H.WellcometoS.Burroughs,(27July1883),WF:S/G/1482.
19
AfterWellcomesarrivalheaddedthe'TallyHo'rangeofperfumes,andMcKesson andRobbinscapsuledpills:TradeMarks187986,WF:85/16.
20 21 22
J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8. J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8.
ForafullaccountoftherelationshipbetweenBurroughsWellcomeandWyethsee FairchildBrothersandFostertoBurroughs,(5November1895),WF:88/47:8.
83
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
84
23 toourignorancethattheBritishhadastandard. ThisledBurroughsWellcometo
appointA.SearlfromHowardsandSons,astheworksmanagerwiththeresponsibilityfor
24 maintainingstandards,andsodefiningtheircommitmenttotheethicalapproach. Inthe
periodbetweenOctober1881andFebruary1884,Burroughswasawayalmostcontinually,
25 establishingthebusinessthroughouttheEmpire.
Meanwhile,HenryWellcometookoverthedailyrunningoftheBritishbusinessand
26 adoptedtheWyethethicalstrategiesandmarketingtechniques. Productswereadvertised
onlyinthemedicalpressasMedicinalFormulaeofnewandimprovedchemicaland pharmaceuticalpreparations,beingofhighquality,andwerepresentedusingthelatest
27 Wyethtablettingandpackagingtechniques. HenryWellcomeabsolutelyrefusedto
advertiseinnewspaperslikethepatentmedicinemanufacturers,ashebelievedthiscreated
28 prejudices,whichthemedicalprofessionhadtosuchacourse. Wellcomeintroduced 29 Americanstyletravellingrepresentativesin1881,sellingonlytopharmacistsanddoctors.
Healsoadoptedthepolicyofsendingoutaround200,000Americanstylecircularsand
23
24
J.WyethtoBurroughsWellcome,(28June1881),WF:88/47. LetterstoG.E.Pearson,WF:E2PFBox23.
25
Radford&FranklandtoH.Wellcome(7January1885),WF:E2PFH.Wellcometo S.Burroughs,(25August1882),Letterbooks18811897,WF:S/G/1482.
27 28 29
G.Pearson,(1936):2. A.W.Haggis,TypescriptHistoryoftheWorks:56.
H.WellcometoS.Burroughs,(9July1885):381,Letterbooks18811897,WF: S/G/1482ForanaccountofanAmericanstyledetailmanseeP.Temin,TakingYour Medicine:DrugRegulationintheUnitedStates (Cambridge,Mass:HarvardUniversity Press,1980):84ff.J.Liebenau,MarketingHighTechnology:EducatingPhysiciansto useHighTechnologyMedicinesinR.P.T.DavenportHines(ed.),History,Bagmenand Markets:StudiesintheHistoryofMarketingandBritishIndustry (Aldershot:Gower, 1986):82101J.Liebenau(ed.), TheChallengeofNewTechnology.Innovationin BritishBusinessSince1850(Aldershot:Gower,1988).
84
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
85
30 15,000samplesoftheirproprietarybeefjuicetodoctors. Doctorswereprovidedwith
remindersofthefirmanditsproductsintheformofmedicaldiaries,pocketpens,pencil casesandpaperknivesbearingthecompanylogoanddrugnames.Pamphletsweresent
31 fromheadofficeandadvertisementswereplacedinthemedicalpress. Further
advertisingtodoctorstookplaceatmeetingsoftheBritishMedicalAssociationorthe PharmaceuticalSocietyandBurroughsWellcomereceivedindependentprizesawardedfor
32 noveldrugsandstandardsofexcellence. BurroughsWellcomehadastandatthe
33 InternationalMedicalandSanitaryExhibitioninLondoninthesummerof1881. Inthe
followingyearsWellcomeextendedtheseinfluencessignificantly,invitingeditorsof
34 scientificjournalsandinfluentialphysicianstoelaboratesocialevents. Someofthese
suchasJ.FletcherMoulton,initiallyadistinguishedmathematicianandbrilliantlawyerand laterLordChiefJustice,thenfirstchairmanoftheMRCwereimportantinsupporting
35 BurroughsWellcome.
30
BurroughsWellcometoJ.Wyeth,(22August1882)and(1February1893),WF: 88/47:8.
31
G.MacDonald,(1980):11,23WellcomeChemistsDiary1906,WF90/19H.J. Parish,HistoryoftheFirmchapters56,WF:85/20:2:105.
32
Exhibitorscertificates,WF:130:973/112.
34
G.Pearson(1936)WF:88/24:41d:48G.MacDonald,(1980):11H.Turner, (1980):810H.J.Parish,Historyof theFirm:56,WF:85/20:2:105H.M.Stanleywas aguestspeakervisitedon21April1884withDr.Manson.ChronicleandDistrictTimes (24April1884).Healsovisitedon14July1900H.M.Stanley,BritishMedicalJournal (12January1890):3257A dinnerforPowerwasheldinJuly1886,WF:YLBox 18BB/86Dr.FrederickB.PowerChemist&Druggist49(25July1896)Letterbooks, WellcometoBurroughs(9July1885):381,WF:S/G/1482Alargecommemorationfor Balfourtookplaceon8December,1902,WF:90:14:2R.C.Sudlow'sretirementdinner wason14September1903,WF:90/14:3Box158.
35
85
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
86
medicinesandtheunsubstantiatedyetextensiveclaimsmadeontheirbehalf,butthe
36 Governmenthaddonelittletoregulatesalesexceptforimposingtaxes. Therewere
affectedBurroughsWellcomeinthreeways:inthefirstplace,they wouldhavehadtopay
39 dutyaswellasthelargeroyaltyalreadypaidtoWyethmakingthemunprofitable.
Secondly,theywouldhavebeenobligedtostamptheirproductsaspatentmedicines,and losetheadvantageofmarketingthemasethicaldrugs.ThirdlytheActwouldalsohave
40 requiredthemtodestroymanyoftheirexistinglabelsandcirculars. Theproposedstamp
dutycameataparticularlydifficulttimeforthecompanytheyhadalreadyoverextended
36
H.WellcometoS.Burroughs,(6September1882),Letterbooks18817,WF: S/G/1482.
39
H.WellcometoS.Burroughs,(14December1883),Letterbooks18817,WF: S/G/1482.
86
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
87
themselvesbyestablishingthebusinessinFranceandSpaintheprofitsforthelastquarter
41 wereonly600againsttheprevious1,800.
AsaresultWellcomehadtodelaypaymentofanoutstandingbillof$5,000toJ. WyethandhecautionedBurroughs:Ihopeyouwillnotarrangeanybusinessmattersin
42 Americathatwilldrawuponusforfundsduringthecomingyear. BurroughsWellcome
alsofacedgrowingcompetitionfortheethicalmarket,includingtheinitiationoftablet
43 manufacturebyotherBritishandforeignfirms. WellcomewrotetoBurroughs:our
competitorshaveneverbeensoaggressiveinpushingbusiness,especiallyinExtractof
44 MaltAllen&Hanburys,Savory&Mooreandothers[were]strikingoutveryboldly.
Secondly,BurroughsWellcomehadtochallengeanumberofinfringementsoftheirown
45 trademarks. Inordertomeetthecrisistheyhadtoextendtheirexistingloansand 46 decreaseadvertising.
41
H.WellcometoS.Burroughs,(30March1883),(15October1883)and(19October 1883),Letterbooks18817,WF:S/G/1482.
42
H.WellcometoS.Burroughs,(26October1883)and(5November1883), Letterbooks18817,WF:S/G/1482.
43
H.WellcometoS.Burroughs,(6September1882),WF:S/G/1482:27(27January 1883),WF:86/98.
45
H.WellcometoS.Burroughs,(22and26October1882),WF:S/G/1482.
87
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
88
47 theirdrugconstitutionsandtheirtablettingmachinery. Wyethagreedonlytolendrather
thansellsomeoftheirtablettingmachinestoBurroughsWellcome,subjecttoa20%
48 royaltyonthesaleofWyethdrugs,andpaymentofthetransportcosts. Nevertheless,the
heinformedBurroughsinSeptember1882that:erectionofmachineryproceeds
51 rapidly. ThreetablettingmachineswerepurchasedfromWyeth,whosuggesteditwould
52 takethreemonthstoinstallthem. AlthoughWellcomeregrettedseparatingtheoffice
47
Letterbooks18811897,(27July1883),WF:S/G/1482. H.WellcometoS.Burroughs,(4December1883),WF:S/G/1482:224.
H.WellcometoS.Burroughs,(19September1882),WF:S/G/1482:2334.
52
H.WellcometoS.Burroughs,(6September1882),WF:S/G/1482:2334J. WyethtoBurroughsWellcome,(14September1882),WF:88/47:8.
88
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
89
andworks,amuchexpandedmanufacturingsiteinacleancountryatmospherewaschosen
53 atBellHouseWharf,Wandsworthin1883.
ThefinancialsituationremainedprecariousasWellcomespentmoreonequippingit
54 thanheoriginallyestimated. Furthermore,hehadbeenunabletoselltheoriginalSnow 55 Hillpremises. WellcometravelledtoAmericainMarch1883tonegotiatethepurchase
offurtherequipmentfromWyethforthenewfactoryandinAprilthefirstpillmachines
56 wereprovided. Howeverduring1883thetensionbetweenBurroughsWellcomeand
53
H.WellcometoS.Burroughs,(12June1883and27August1883),WF:S/G/1482.
Twopillmachines,alatheandportablefurnaceweretobesenttoBurroughs WellcomeduringApril,J.WyethtoBurroughsWellcome,(10April1883),WF:84/7:8.
57
WellcometoBurroughs,(13March1883,27July1883),WF:S/G/1482.
89
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
90
Wyethdemanded50,000forthisprivilegeand,whenagreementcouldnotbereached,
58 theyaskedforthereturnoftheirtablettingmachines.
specialsattherequestofphysiciansandbegantoconcentrateonlargescaleproduction
61 ofasmallernumberoflines.
62 WyethcontinuedtocriticiseBurroughsexpensesasexcessive. Neverthelessduring 63 thefirst3yearsofbusiness,salesgrewfrom17,811in1881to57,156in1883. By 64 1884,10,000hadbeeninvestedinthecontinentalbusiness. Burroughsmeanwhile
58
Mr.C.BargatetoH.A.D.Jowett,HistoryoftheWorks,(26November1930), WF:YLBox15WF84/7.
60
DrWittejoinedinsummer1882andwasplacedinchargeofdevelopingthe Wandsworthsitein1883,Letterbooks,(27July1883),WF:S/G/1482:98.
61
62 63
64
90
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
91
65 becameincreasinglycriticalofWellcometowardstheendof1883. Wellcome,inturn
wasaggrievedthatinitialpromisesofanequalpartnershiphadbeenunfulfilledandthat Burroughsmademajordecisionswithouthim.Wellcomecriticisedhishastyflashesof
66 judgmentandimpulsiveandalltoohastydisposition. Theriftsimmeredthensettled 67 temporarilywhileanewpartnershipagreementwasdrawnup.
CentraltotheirstrategywastheadoptionofthetrademarkTabloidproposedby WellcomefortheirspecialtabletsregisteredfirstinBritaininMarch1884andthenin
69 variousoverseascountries. Tabloidwasinitiallyderivedfromacontractionoftheterms
65
TabloidsandTabletsChemist&Druggist40(28May1892):785Tabloidsand TabletsChemist&Druggist40(4June1892):817BurroughsWellcome,Tabletsand
91
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
92
totheChemist&Druggist,thewordTabletswasappliedbyustothisclassof (compressed)drugsatthecommencementofourbusinessin1878.Thisformofmedication
71 hadhithertobeenknowninthiscountryascompressedpills. Tabloids,howeverwere
furtherdistinguishedbyemphasisingthatthetabletscontainedstandardiseddosesof
72 purifiedactivedrug,measuredwithgreataccuracy. Thisbecamethecentraldefining
conceptofBurroughsWellcomedrugs,emphasisingthattherewasgreateractivityandless variabilitythanotherfirmspreparations.Tabloidswerepromotedinthismanneratthe
73 annualBritishMedicalAssociationmeetingwithgreatsalesasaresult. Bytheendof
1884Henry Wellcomereported:Ourbusinessisprosperinghandsomelyandtheoutlook
74 moreencouragingthanever. BurroughsWellcomecontinuedtolicenseinnew 75 productsin1885actedasagentsforFairchildsDigestiveFerments.
ThenewpartnershipbetweenBurroughsandWellcomewasfinallyagreedon29May
76 1885. Buttheriftbetweenthemsoonwidenedagain,andinJuly1886Burroughssued 77 forbreachofpartnership. HeclaimedthatWellcomehadnotdiligentlyappliedhimself,
72 73 74 75
WellcometoFairchilds,(16June1885),WF:E2.BytheendofOctober1885the firmheldabalanceof3,300,Letterbooks,(26October1885),WF:S/G/1482.
76 77
Radford&Frankland(solicitors)toWellcome,(7January1885),WFE2.
92
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
93
78 thathehadunpaiddebtsandthathehadwithdrawnexcessprofits. Incontrast,allofthe
evidencepointstoextensivedaytodayinvolvementofWellcomeinmanagingand reorganisingthebusiness,whileBurroughsplayedoutanequallyimportant,butquite
79 differentroleinopeningupnewoverseasmarketsandlicensingnewproducts.
Burroughswasthemostwidelyknownpersonalityintheranksofpharmacy,andwell
80 knownthroughouttheworld. Wellcomeretortedthatthefirmhadbeenanentangled
snarlwhenhetookoveroperations,whichifithadbeenleftwouldhavebeenruined.
81 HeindignantlytoldBurroughsyounolongerknowthebusiness. Wellcomeechoed 82 WyethwhohadalsocomplainedofBurroughswantofasystem. Nevertheless,
Wellcomehimselfhadbeenabsentfromworkformuchof18856,butonlybecausehehad
83 almostdiedwhileheroicallysavingaladyfromdrowning.
In1886Wellcomewrote:Businessisinthemostwretchedlydepressedstate throughoutEuropeandtheColonies,weareholdingourown,simplifiedbygivingupthe
84 McKessonRobbinspills,thelonglistofwhichhasbeensomethingofanencumbrance.
78
AnoverseasofficewasestablishedinSydneyin1886andothersfollowed.WestKent Advertiser(21March1924),WF:Box25.
80
Chemist&Druggist46SilasBurroughsObituary(9February1895):213(18May 1895):675.
81
H.WellcometoS.Burroughs,(25August1882),Letterbooks18811887,WF: S/G/1482.
82 83
J.WyethtoH.Wellcome,(28June1881):213,WF:88/47:8.
H.WellcometoJ.Wyeth,(8January1886),Letterbooks18811887,WF:S/G/1482: 438.
93
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
94
85 formsofnauseousdrugssuchaspotassiumiodide. Theyalsoincorporatedthelatest
suppliesofrawmaterialsofcertainplants. By1880ParkeDavisofPhiladelphiawasprobablythemostsophisticatedAmerican manufactureroftablets,havingovertakenWyeth.Successinbusinesswasdeterminedby differentiationagainstotherfirmsproducts.Whileproducingbettertabletswasone possibility,ParkeDavisidentifiedanewmethodbyintroducingalaboratoryin1879asa majorcommitmenttopurityandstandards.UnlikeGermanlaboratories,whichfocussedon newproducts,theParkeDavisapproachwastoproducepurestandardiseddrugsfrom complexextracts.In1880theyhiredthechemistAlbertLyonswhodevisedamethodto standardiseergot,analkaloidcontainingproductofafungusthatgrewonrye.For centuriesergotextractswereknowntopreventbleedingafterchildbirth,butthedownside wasthatcontaminatedryewheneatencouldalsocauseepidemicsofgangreneand
88 convulsions,soitwasimportanttoknowthepotency. By1883ParkeDavishad
assignedpharmacologicalactivitytoaparticularcomponentwithinergotandbegan to
85
H.WellcometoJ.Wyeth,(8January1886and18May1886),WF:88/47:8.
C.DeCosta,St.AnthonysFireandLivingLigatures:aShortHistoryof ErgometrineLancet(18May2002):176870.
94
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
95
89 standardisetheirproducts. From1886thesuccessfulpolicyofincorporatinghighly
activestandardisedpreparationsintheirtabletswasextendedtootherdrugs. InordertoremaincompetitiveBurroughsWellcomehadtoextricatethemselvesfromthe
90 arrangementswithWyethandtheyfinallyachievedthison5November1888. Bythis
creatinganichemarketwithinthegrowingpharmaceuticalindustry:thoughtheystilldid notmanufacturechemicalsonalargescale,asinGermany,theydidincorporate
89
H.WellcometoJ.Wyeth,(5November1885),WF:88/47:8.
95
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
96
manufacturedchemicalsintotheirtablets.BurroughsWellcomewasstillsmallbyGerman
93 standardseventhoughtheirstaffincreasedsixfoldinthe7yearsupto1891.
93
11.
96
96
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
97
97 theintestine. In1892theircompetitorsAllen&Hanburysintroducedsolublecoated
pills,disintegratingtabellaeofcompresseddrugs,andeasilysolubletabellaeforthe
98 preparationofhypodermicinjections.
HenryWellcomecontinuedtoadoptnovelmarketingtechniquesandspecialities
99 weresoldtoprestigecustomersinconvenientmedicinechests. Heproudlyboastedthat
they:haveequippedeverycommercial,military,mining,exploringandotherexpeditionof
100 importancewhich haslefttheseshoresformanyyearspast. ByAugust1893,four
yearsafterthemovefromWandsworth:thenewworkswereconsiderablyenlargedand fittedupinamostelaboratescale,onalevelwithanysimilarfactoryintheWorld.Itwas
101 awellventilatedfactorywithaconstantatmosphereof60degrees.
Anexternalphysiciansuggestedthistechnique,TradeNotesMessrs.Burroughs Wellcome&Co.Chemist&Druggist40(11June1892):847.
98
GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen&Hanburysand theBritishPharmaceuticalIndustry17151990(London:Murray,1990):102103.
99
100 101
102
103
97
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
98
speciesofplant,grownunderdifferentconditionsandharvestedatdifferenttimeswere mixedtogether.Thestrengthcouldonlybecomparedbymeasuringthetotalalkaloid content,astheactiveingredientswereunknownbuteventomeasurethetotalalkaloidal strengthrequiredlaboratoryexpertise. HenryWellcomeestablishedtheWPRLin1894tostandardisethepreparationof diphtheriaantitoxin.Hesoughtameansbywhichhecouldshowthathisfirmsextracts werethemostpotentandheappliedthesamethinkingtoergot.Hewasimpressedwith ParkeDavisclaimsofstandardisingergotbyabiologicalreaction,recognisingthatdoctors wouldalsobeimpressedinbeingprovidedwithareliableproductfreeofthesideeffects causedbyotheralkaloidspresent.Wellcomedeterminedtofollowtheirleadandemployed furtherchemistsandphysiologistsinestablishingtheWellcomePhysiologicalResearch
104 Laboratories(WPRL)in1894. ThismajorcommitmentwouldsetBurroughsWellcome
104
98
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
99
butthenhetravelledextensivelyasBurroughshadandestablishedthebusinessinAustralia,
106 SouthAfrica,Italy,CanadaandtheUSA.
manufacturinginBritaininvolvedonlyincorporationofdrugsprovidedbyWyeth,though
106
G.E.Pearson,(1936)WF:88/24:41d:5G.Pearson,WF:YLBox23E2PF.
107
ProgressinPharmacyChemist&Druggist36(28January1888)pageunknown foundinWF:89/29:7.
110
ForexampletheytestedExtractumpancreatitisofSavoryandMoore.H.Wellcome toFairchilds,(16June1885),WF:88/47:8.
99
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
100
111
112
TradereportsBritishMedicalJournal (3August1895):294295.
PowerArchives,WF:88/94:59.
100
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
101
Wellcome,Powerhadareputationasaworldauthorityonplantalkaloids.Wellcomehad keptintouchwithhisfriendPowerandvisitedhisresearchlaboratoryinStrasburgand
117 knewhewastheidealmantoleadBurroughsWellcomeintonewavenuesofresearch.
115
GeoffreyTweedale,(1990):6165. G.MacDonald,(1980):7.
116 117
101
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
102
assistantH.A.D.JowettfromthePharmaceuticalSocietylaboratory.Jowetthadrecently gainedhisD.Sc.fromLondonUniversityafterworkingonthesmallscaleextractionand
120 characterisationofalkaloids. Hehadcarriedoutnoteworthyinvestigationsofnatural 121 productsofmedicinalinterestunderProfessorW.R.Dunstan. UnderPowerhe
TheanalyticallaboratorywasestablishedasanindependentsectionwithintheWCRLin
125 February1897,headedbyDr.F.H.Lees. E.F.Harrison,whohadalsotrainedunder
119
F.B.Power,WCRLWF:88/94.
120
H.King,FrankLeePyman(1944):682T.A.Henry,WyndhamRowland Dunstan(1950):6381.
122 123
WellcomeResearchLabsDinnertoF.B.Power,(21July1896),WF:88/94:79a.
ADayinDoverChemist&Druggist52(25June1898):954.
102
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
103
theanalyststhat:Thesecuringofchemicalsofthefinestqualityandofthehighestpurityis
129 theprimeraisondtre,butthequestionofprofitmustneverbelostsightof.
126
J.K.Irvine,TheParttheChemistPlaysinNationalHealthInsurance PharmaceuticalJournal (1February1930):101102 Pharmaceutical Journal (8February 1930):12930E.F.Harrison.LaboratoryBook,WF:88/94:26MetallicImpurities:Tests ofBlaud'sPills,WF:89/29/1(1887)L.G.Matthews,HistoryofPharmacyinBritain (Edinburgh:E.&S.Livingstone,1962).HarrisonbeganasaJacobBellscholarin1890, qualifyingthenextyearandgainingaBScfromLondonUniversityin1892andthe AssociatedexamoftheInstituteofChemistry.In1905hebecameafellowoftheInstitute ofChemistry,WF:88/94:26.
127
G.Pearson,(1936)WF:88/24:41dMr.Hogg,OrganisationoftheWellcome ChemicalResearchWorks,Dartford18971934,WF:89/57:13.
129
103
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
104
theaimisforimprovedqualityandnottorelyontheproductsofothersandunderno circumstanceswhatevermaydrugsetc.purchasedoutsidebeuseduntiltheyhavebeen
131 passedbytheanalyst. ItisclearthatthepromotionofBurroughsWellcomeproducts
accordingtostandardisationandpuritywasnotonlyapromotionaltool,butwastaken veryseriouslyinternally. HenryWellcomerecognisedthattherewerevariousmeansbywhichhecouldclaim hisproductswerebetterthancompetitorextracts.Thefirstwasbyensuringareliable sourceofrawmaterialsupply.InthisrespectPowerwasimportantincheckingthespecies, sourceandqualityofpurchasedalkaloids.Evenbetterwastogrowtheplantsrequired locally.Thesecondwastostandardisechemicallytheconditionsofextractionandtouse reliablestrengthsofsolventsfortheprocess.Leescheckedtheseintheanalytical department.Athirdmeanswastopreparedifferentsaltsofthealkaloidstoimprovetheir physicalpropertiesandtheircompressibilityintotablets.Thiswaspartoftheworkofthe Chemicallaboratory.Afurthermeanswastoimprovetheassayofalkaloids.Inthepastthe totalamountsofalkaloidsextractedhadbeenmeasuredbutaschemicalconstitutionswere definedtheindividualalkaloidscouldbemeasured. PowerandJowettandtheirstaffpurifiedandcharacterisedthechemicalstructures ofthemanyalkaloidstheyextractedandworkedouthowtosynthesisethem.Subsequent extractscouldthenbecomparedagainstasyntheticstandardtoshowhowmuchactive ingredienthadbeenextracted,inaclosecollaborationbetweentheWPRLandWCRL From1898Schryver,PowerandJowettpreparedmanyalkaloidssyntheticallysothat alkaloidalextractsfromplantscouldbestandardisedagainstanabsolutestandardbefore
132 incorporationintotablets. Thefinal stepwastoscaleuptheseprocessessothatstaffat
130 131
Ibid.
WF:89/57IIIIH.Wellcome,ChemicalDepartmentalInstruction3(29 November1898)volumeii,inWF:S/G/145.
132
StaffWCRL,WF:YLBox25.
133
B.CARRF.H.LaboratoryNotebooks.ImperialInstituteofScienceandTechnology 2132B/CARR/1vols.IandII.
104
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
105
WellcomecharacterisationsofnaturalproductswerepublishedintheJournalofthe SocietyoftheChemicalIndustry. Initially,thechemistryattheWCRLinvolvedonlysimplehydrolysis,condensation orsubstitutionreactions,butoverthenextdecadethecomplexity ofchemistryperformed increaseddramatically.TheWCRLstaffcharacterisednaturalproductssuchasthebarkof Cascarasagrada,(Rhamnuspurshianus),extractsofwhichhadbeenusedasapurgative, andevaluatedthechemistryofresins,volatileoilsandcrystallineextractstoestablishwhat wasresponsibleforthebiologicalaction.137 AsthisworkincreasedtheWCRLexpandedfurthertooccupyanadditionalfloorof theSnowHillsite,whichremainedthelocationuntilthemoveon24May1899to completelynewpremisesat6KingSt.,SnowHill.Thenewlaboratorieswereequipped withpumps,vacuumfilters,electricsupplies,distillers,analyticalbalances,adarkroomand adrymill.Thelibrarywasstockedwiththekeyjournalsreportingadvancesin chemistry, suchastheJournaloftheChemicalSociety,BerichtederDeutscheChemische
134
G.Pearson,(1936),WF:88/24:41d:7. WellcomeResearchLabsDinnertoF.B.Power,(21July1896),WF:88/94:79a.
105
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
106
138 Gesellschaft,ChemicalNewsandtheJournaloftheSocietyoftheChemicalIndustry.
Astheworkbecamemorespecialisedadepartmentwasestablishedforthe preparationofalkaloidsandsynthetics,separatefromthoseproducinginorganicchemicals
139 andgalenicals. Jowettsworkthereonthealkaloidsof Jaborandifrom1899was
describedaspioneeringandledtotheisolationandproposalofthechemicalstructureof theactiveingredient,pilocarpinein1902andvariousfurtherchemicalderivativeswere
140 isolatedandinvestigatedforphysiologicalactivity. Jaborandileaveshadenteredusein
medicinein1874,slowingtheheartandincreasingsalivarysecretions,buttherehadbeen
141 someconfusionoverthebestspeciesofplanttousetoprepareextracts. Theworkof
Manynaturalextracts,syntheticderivativesofmorphine,newcreosotecompoundsand
138
G.Pearson,(1936),WF:88/24:41d:7.
H.A.D.Jowett,YearBookofPharmacy 36(1899):435 JournalofChemical Society 77(1900):474,851 JournalofChemicalSociety 79(1901):581,1331H.King, F.L.Pyman(1944):682H.A.D.Jowett,PilocarpineandtheAlkaloidsofthe JaborandiLeavesJ.Chem.Soc.(1900):47398H.A.D.Jowett,TheAssayof PreparationsContainingPilocarpineandtheCharacteristicsofPilocarpineNitrateand HydrochloridePharmaceuticalJournal (29July1899):9193.
141
106
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
107
newsaltsofolderagentsrequiredbiologicalstandardisationinanimalsattheendof
143 1900. ThisworkcouldnotbeperformedwithinBurroughsWellcomeuntiltheHome
144 OfficelicensedtheWPRLlaboratoriesin1901.
LargescaleextractionstookplaceattheChemicalWorksinDartford,whichwere
145 considerablyenlargedwithafloorspaceof100by45feetinJuly1896. TheWorkshad
143
E.M.Tansey,(1989):141. G.Pearson,(1936)WF:88/24:41d:7.
146
SilasBurroughsObituaryChemist&Druggist46(8February1895):213A.W. Haggis,HistoryoftheWorks:56,WF:85/20:2:1.
147
Carr'sarchivesareatImperialCollege,B.CARRFH6includingnotesofa conversationwithbyA.E.GuentherT.A.Henry,W.Dunstan(1950):6281.
107
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
108
furtherformercolleaguesfromDunstanslaboratorywhohadtrainedatFinsburyCollege,
149 includingW.C.ReynoldsandW.E.Thompson. Theyperformedbiochemicaltestson 150 Soloids,assayedchaulmoograoils,glycerophosphates,samplesfromthecolonies, plants 151 grownatDartford,andtestedmanufacturedbatchesagainstsyntheticstandards.
FivefurtherchemistryassistantsjoinedtheWorksbetweenNovember1897and October1899,includingonewhotransferredfromthePharmacydepartment,butthese
152 wereunqualifiedboys. BurroughsWellcomeopenedanothernewFinechemical
buildingon6June1898toproducechemicalintermediatesandinorganicsaltsand BurroughsWellcomehadjustcompletedalargebuildingand(were)layingfoundationsof
153 another58feetby130feetwith3storeys. InDecember1898amaltbrewingplant
148
A.Findlay,WilliamHobsonMills(eds.),BritishChemists(London:TheChemical Society,1947):5897.
149
WilliamColebrookReynoldsjoinedtheworkson1April1899andreportedtoCarr. Helefton3November1911:Mr.Hogg,OrganisationoftheWellcomeChemical ResearchWorks,WF:89/571III.W.E.Thompsonjoined1August1899.Previouslyhe hadworkedasalabboyatthePharmaceuticalAssociationbeforegoingtotheImperial Institutewherehedidnoformaltrainingexceptfor3yearsunderCarr.AtBurroughs Wellcomehepreparedalkaloids,eserine,andpilocarpineattheExperimentallaband WCRLanddepartedinJanuary1916 JohnAugustusGoodsonwhojoinedtheTropical InstituteinKhartoumin1906andlaterworkedattheWCRLalsotrainedatFinsburyunder RaphaelMeldola,WF:YL Box25.
150
W.DunstantoBurroughsWellcome,(17February1906),WFBusiness correspondence18951940,WF:D3DWEG.E.Pearson,(1936),WF:88/24:41d:7.
151
152
Laboratoryreports18891893,(10October1889),WF:84/7.
108
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
109
electricpower,anelectriccrane,motorvans,workstelephonesandapackaging
156 conveyer. Anewchemicalbuildingwasopenedin1901,afurtherTabloidbuildingin
1903,achemicaldepartmentofficein1904,anengineeringshopandaplanttoproduce chloroform.ThelaboratoriesimpressedvisitingSocietyoftheChemicalIndustrymembers
157 on15July1905andanotherplantforarsenicalsopenedin1908. Intheperiodfrom
1896totheoutbreakoftheFirstWorldWar,theWCRLandthemanufacturingcapacityat theWorksweresignificantlyenhanced. 3.4TheWellcomePhysiologicalResearchLaboratoriesupto1901. InthissectionontheWPRLpriorto1901Iwillintroducethekeycharactersand showhowtheWPRLandWCRLinteractedtoutilisechemistrytodifferentiateBurroughs Wellcomeproductsbaseduponpurityandstandardisation.Ihavedemonstratedalready thatBurroughsWellcomehadbeenpursuingachemicalapproachsincetheinceptionof Tabloidsin1884. EmilvonBehringsdiscoveryofdiphtheriaantitoxininGermanyin1890was recentlydescribedbythehistorianWilliamBynumasprobablythesinglemostimportant catalystinthecreationofthemodernpharmaceuticalindustry,becauseitstimulatedthe searchforabetterunderstandingoftherelationshipbetweenthestrengthandpurityofa
158 preparationanditsaction. Diphtheriaantitoxincouldbeproducedinanylaboratorythat
hadthefacilitiestoraiseandassayitinanimals.Nothavingalicence,BurroughsWellcome
154
B.CARRFH6Mr.Hogg,WF:89/57IIII.
WFBox77,51D3DWandMr.Hogg,WF:89/57IIII.
158
W.F.Bynum,ScienceinthePracticeofMedicineintheNineteenthCentury, (Cambridge:CambridgeUniversityPress,1994):164165.
109
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
110
triedtonegotiatetherightstodistributediphtheriaantitoxinproducedbytheBritish InstituteofPreventativeMedicine(BIPM)butwhiletheyprevaricatedandAllen&
159 Hanburystookupthatrole,BurroughsWellcomedecidedtomaketheirownsupplies.
toperformsuchworkinBritain.TanseydiscussedindetailtheimplicationsoftheActfor BurroughsWellcomeandthedeterminedeffortstoovercometheinitialrejectionofthe
161 BurroughsWellcomeapplication. 162 TheyproducedtheirowndiphtheriaantitoxinfromApril1894. Anindependent
productionofdiphtheriaantitoxinbeganinthefirstweekofJanuary1895,aheadofthe
164 BIPM. BurroughsWellcomeinitiallyprovideditfreeofchargeduringtheperioditwas 165 166 underthetrial. Theyalsopreparedaconvenientdriedconcentratedversion.
159
160
GeoffreyTweedale,(1990):120. J.Liebenau,(1987):72,75,100,110.
161 E.M.Tansey,(1989):141.
162
G.Pearson,(1936),WF:88/24:41d:4.
163
A.W.Haggis,HistoryoftheWorks:56,WF:85/20:2:4(14January1899),WF: 86/92:1TheDiphtheriaCureChemist&Druggist46(16February1895):238Trade
110
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
111
AssalesofantitoxinincreasedHenryWellcomeappliedtotheHomeOfficefora licencetoperformphysiologicaltestswithinthefirm,buttheirapplicationwasturned
168 downinAugust1896onthegroundsthatitwouldcreateamonopoly. TheWPRLat 169 CharlotteStreetinLondonwasextendedtoincreaseproductionofantitoxin.
BokenhamcouldnotcopealonewiththeincreasingworkloadandWellcomesought assistanceinitiallyfromFrederickGowlandHopkins,whodecidedtopursuehisacademic
170 career.
InsteadWellcometurnedtoProfessorMichaelFosterinCambridge,theforemost
171 physiologistinBritainforadviceonstaff. Fosterrecommendedhisownresearch 172 pathologistA.A.Kanthack, butWellcomesecuredtwoCambridgegraduates.Walter
NotesChemist&Druggist46(22June1895):870AngloAmericanNewsletter(1896): 1612,WF:E2.
166 167
TradeNotesChemist&Druggist45(1894):857WF:YLBox23(E2).
WPRLDiagnosticFeesMemo's,(1May1901),andH.WellcometoDrBousefield (21December1903),WF:YLBox84.
168 169
E.M.Tansey,(1989):141,especiallyonpp.1718,23.
A.W.Haggis,TheLifeandWorksofHenrySolomonWellcome,WF:89/72IIII.
111
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
112
Despitetheproblemofgettingassaysdone,BurroughsWellcomesoldnotonly diphtheriabutalsoantisyphiliticandantityphoidantitoxins,andantistreptococcus
176 sera. InanticipationoffurtherexpansionoftheWPRL,atBrockwellHall,asiteat 177 HerneHillwasleasedfromNovember1898. Inthespringof1899theWPRLmoved 178 thereandDowsonrecruitedyoungscientistsfromthelocalschoolinDulwich. The
headmaster,HerbertBreretonBakerwasachemistwithahighreputation,whowaslater
ScientistsandDoctors:MedicineatCambridge18001940(Cambridge:BoydellPress, 2000):1526,16365,172,196.
173
G.E.Pearson,(1936),WF:88/24:41d:7.
112
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
113
J.SudmersenjoinedBurroughsWellcomeasassistantsinthebacteriologylaboratoryand
180 continuedtheireducationintheevenings. Afurtherchemist,ArthurJamesEwinswas 181 recruitedtotheWPRLfromthesameschool.
HomeOfficeinspectorvisitedthesitehedidnotattempttoconcealhissatisfactionhe
184 hadnotseenanythinglikeitinBritain.
TheapplicationfortheHomeOfficelicence
wasfinallyacceptedon5September1901makingthephysiologicaltestingofantitoxins
185 preparedattheWPRLfinallypossibleonsite. Onlyoneotherfirm,JohnRichardson&
Co.,whoestablishedtheBacteriologicalInstituteinLeicester,appliedsuccessfullyfora
186 licenseanditwasnotuntil1905and1908thatfurtherlicensesweregranted. TheHome
179
H.WellcometoC.T.RitchieM.P.,(25February1901),WF:86/92:1:5.
C.L.Oakley,A.T.Glenny(1966):16380H.J.Parish,HistoryoftheFirm:56, WF:85/20:2:6.
184
WellcomePhysiologicalResearchLaboratoriesChemist&Druggist55(11 November1899):780781.
185
186
C.S.MurdochtoBurroughsWellcome,(21May1900),WF:86/92:1. E.M.Tansey,(1989):141.
113
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
114
OfficelicensegaveBurroughsWellcomeaclearadvantageoverEvans&SonsandAllen& Hanburyswhostillreliedonexternalsuppliesofantitoxinorhadtohaveeachbatchtested
187 elsewhere. ThesalesofdiphtheriaantitoxinbyBurroughsWellcomerosedramatically 188 from84,000vialsin1905to239,000in1910,and627,000in1915. Themainpointsto
emphasisefromthisdiversionintotheWPRLarethatBurroughsWellcomecontinuedto employscientists,theirscientificreputationwasenhancedandtheycontinuedtheirdrive towardsstandardisedmedicines.Inadditiontoantitoxins,thelicensingofthelaboratories allowedthemtofurtheradvancetheirworkonpurifying,andcharacterisingalkaloidsand glucosidesextractedfromplantsandorganextractsfromanimals,sotheycouldcompare thebiologicallystandardisedpreparationswithsyntheticallypreparedequivalents. 3.5InteractionsBetweentheBurroughsWellcomeLaboratoriesandWorksafter 1901. BurroughsWellcomeobtainedtheirvivisectionlicense,conditionalupontakingonan additionalphysiologist,whichWellcomeagainarrangedthroughhiscontactsatCambridge University.JohnMellanbyofEmmanuelCollege,Cambridge,qualifiedinphysiologyand chemistryin1900underMichaelFoster,J.N.LangleyandF.G.Hopkinswho
189 recommendedhisappointmenttothestaffoftheWPRLinOctober1901. Afurther 190 pathologist,Dr.W.V.ShawfromSt.MarysHospitalwasappointedinJanuary1902.
BurroughsWellcomealsocollaboratedwithaDr.HamiltonofDartfordandthepreviously mentionedDr.Bousefield,apathologistatSt.BartholomewsHospitalinLondon,where
187 188
189
ShawwasappointedinJanuary1902:E.M.Tansey,(1989):356.
114
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
115
ThegrantingoftheHomeOfficelicenceopenedthefloodgatesforthefirmto
195 evaluateabacklogofpreparationsrequiringassayinanimals. Thisencouragedthefirm
191
G.MacDonald,(1980):35.
115
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
116
andhyoscyaminefromplants,wascontrolledbydevelopingmethodstoassaythe concentrationsofactiveingredients.Firstlythiswasbysimplytestingtheextractsin animals,butthencruciallythiswastakenonestepfurtherbysynthesisingtheproposed activeingredientstoprovetheiridentitytotheextracts.Oncethiswasachievedthe chemicallysynthesisedpreparationweremaintainedasatechnicalstandard.Thiswas importantbecausetheextractionmethodusedbyotherfirmsproducedextractsofvariable activity,despiteattemptstostandardiseproceduresandconditions.Furthermorethepure chemicalcouldthenbeusedtoevaluatethemoresubtleactivitiesofthedrugin physiologicalexperiments.Becauseofitspurityitcouldbeusedatlowerdosesand untowardreactionsfromadditionalalkaloidsinanextractcouldbeexcluded.Furthermore, chemicalhomologuescouldbepreparedtotesttherelationshipofchemicalstructureto activity.ForthefirsttimeaBritishfirmsoldorganicdrugsaccordingtothestrengthof theirpureactiveprinciplesratherthanthetotalalkaloidcontentwithouthavingtorelyon externalsupportforassaysastheyhadwithDunstan.Thewholeprocesswas commerciallydriven,aimingtoproducenovelpreparationsthatweremoreactive,more concentrated,morepotentormorepure,givingBurroughsWellcomeadifferential advantageoverotherfirms.Encouragedby earlysuccessesthefirmpreparedfurtherde novosyntheticchemicals,whichwerealsotestedforphysiologicalactivity. Inadditiontoplantextracts,Jowettpreparedthehumanhormone,adrenaline,for
196 testingintheWPRLin1903. Howeverinsteadof sellingadrenalineincompetitionwith
EmeritusProfessorattheRoyalCollegeofScienceinKensingtononresearchregarding
196
116
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
117
throughhisroleontheSocietyfortheChemicalIndustrybutalsowithtopchemists
199 throughoutEurope. CarrsmentorHenryArmstrongturnedtothefirmforassistancein 200 workinguparatherlargequantityofmaterialforwhichIhavescarcelytheappliance.
Thenovelchemicalsorroutesofsynthesiswerepatentedtosecureprotectionfrom
202 otherfirmscopyingthem. Patentingandtestingtheseproductsinanimalsgave
W.A.TildentoF.B.Power,(13June1906),WF:88/94:41.
H.E.ArmstrongtoF.B.Power,(11July1907),WF:88/94:41. AlexanderFindlay,andWilliamHobsonMills(eds.),BritishChemists(1947).
FrankPymansnameappearedwiththatofWellcomeonseveralpatentse.g. ManufactureofNewTherapeuticCompounds(PhenylarsonicAcids)BritishPatentBP 855(1908)ManufactureofaNewTherapeuticCompound(fromLaudanosine),BP314 (1909)ManufactureofNewTherapeuticCompounds,BP11108,13828,14633(1909) TherapeuticCompound,Thiolaminomethylglyoxaline,BP25,873(1910)physiologically activebase4(or5)betaaminoethylglyoxyline,BP28,538(1910).Wellcomepatented withF.H.Carr,Manufactureofemetine,BP14,677and17,483(1913)Wellcomealone patentedaminophenylselenonicacid,BP2787(1914),C.M.Wenyon,HenryWellcome, ObituaryNoticesofFellowsoftheRoyalSociety 2(1938):229238.
117
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
118
BargersbotanicalandchemicalexpertiseenabledresearchersattheWPRLtoexaminethe chemicalconstitutionoffurtheralkaloidsandglycosideshisfirstpublishedresearchat
206 BurroughsWellcome(withW.V.Shaw)wasontheconstitutionofdigitalisextracts.
ThescientificstatureoftheWPRLwascementedbytheappointmentofHenryHallett Dalein1904.Dowson,Barger,MellanbyandDaleallcamefromWellcomesconnections
207 withFrederickGowlandHopkins,whoactedasaconsultantandWalterFletcher. Dale
hadstudiedexperimentalphysiologyinMichaelFostersprestigiousdepartmentat
208 Cambridgebetween1894and1900. HeknewBargerfromCambridgeasamemberof
theNaturalScienceclub.SincethenDalehadperformedresearchinEhrlichslaboratoryin
203
W.J.Reader,ImperialChemicalIndustriesaHistory.TheForerunners18701926 volume1(London:OxfordUniversityPress,1970):199.
204
JohnP.Swann.(1988):31RichardHarrisonShryock,AmericanMedicalResearch PastandPresent(NewYork:TheCommonwealthFund,1947):140.
205
206
H.H.Dale,GeorgeBarger(1940):6383.
TheChemicalandPhysiologicalAssayofDigitalisTincturesPharmaceuticalJournal 19(1904):249.
207
H.H.Dale,Reminiscences:WPRL19041914,DaleArchives,93HD143.6.
208
118
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
119
Parkfittedforchemistryandbacteriologyresearchandsetaboutaresearchcareerthat eventuallybrokedownsuchbarriers.
209
H.H.Dale.Reminiscences:WPRL190414,DaleArchives,RoyalSociety93HD 143.6:23
213
H.H.Dale,ReminiscenscesWPRL190414,DaleArchives,RoyalSociety93HD 143.6:8.
119
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
120
In1904MarmadukeBarrowcliffjoinedtheWCRLfromNottinghamUniversityand
214 workedonthechemicalconstitutionofvariousessentialoils. AtSudlowsretirement
dinnerin1905,WellcomestatedthatsinceSudlowhadstartedin1879,thepremisesofthe
215 firmhadincreased800foldandthestaffwasnowat4,300. Inordertodealwiththe
increasingspecialisationofwork,theWCRLestablisheditsownExperimentaldepartment inDecember1905.AlthoughJowettwasitsmanager,itwasPymanwhoranthe
216 laboratoryonadailybasis. FrankLeePymanwasanexperiencedchemistwhojoinedthe
laboratorystaffoftheExperimentallaboratoryinFebruary1906.Hehadgraduatedfrom VictoriaUniversity,Manchester,andafteraperiodofresearchinZurichUniversitytook
217 upashorttenureinthelaboratoryofThomasEdwardThorpe,theGovernmentchemist.
218 Aprewarmaximumofninechemicalstaffwasreachedin1906.
214
R.C.Sudlow'sretirementdinnerwason14September1905,WF:90/14:3.
216
Mr.Hogg,WF:89/57IIII.
120
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
121
Pymansteamimmediatelypreparedsyntheticderivativesofsalicylicacid,whichBurroughs Wellcomepatented,exploredinanimalexperimentsandsoldaspotentialalternativesto
220 BayersAspirin. Aspirinwasagreatsuccess,butthereweremanypoorsubstitutes,
whichBurroughsWellcomedemonstratedwereveryvariableinfreeacidnumber,iodine
221 absorptionandmeltingpoints,especiallythosefromtheGermanmarkets. Pyman
synthesisedberberine,andphenacetinbeforetakingupJowettspioneeringinterestin glyoxylines,(thealkaloidsofthePilocarpussp.)andisolatedjaborine,pilocarpidine,
222 pilosineandpilocarpine,extendingtheresearchintosyntheticmodifications. Asthe
workoftheWCRLexpandedoverthenext10years,asteadystreamofnewrecruits
223 joined.
219 220
H.King,FrankLeePyman(1944):683.
C.EdwardSagetoF.B.Power,(10June1904),WF:88/94:58(quote)W.Dowson toBurroughsWellcome&Co.,(23January1901),WF:94:36.
222
121
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
122
that:Wecanonlyhopetobethefirstinthefieldandgetthecreditofthescientific
225 investigationandwecannotobtainamonopolysuchaswecouldwithasyntheticdrug .
Tropicalmedicineplayedanimportantroleincolonialexpansiontowardstheendof thenineteenthcenturyasseveralcausativeagentsofinfectionwereidentified,togetherwith
224
HenryWellcometoW.Dunstanandreplies(17,20,27,28February1906),Business Correspondence18951940,WF:D3DWE.Thequoteisfrom27February.
225
H.King,FrankLeePyman(1944):68384.
ListofProductsinOrganisationoftheWellcomeChemicalResearchWorks,Mr. Hogg,WF:89/57IIII.
122
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
123
WellcomeTropicalResearchLaboratorieswereestablishedattheGordonMemorial
230 CollegeinKhartoum,Sudanin1902. AswiththeWPRLandWCRL,HenryWellcome
attractedtopscientists.ThefirstDirectoroftheTropicallaboratorieswasDr.(laterSir)
231 AndrewBalfourwhohadtrainedinEdinburgh. Afloatinglaboratorywasaddedin1907
232 underDr.CharlesMorleyWenyon,whoreturnedtoEnglandin1908, andafurther 233 tropicaldiseasesexpert,Dr.CecilA.Hoarewasemployed. Wenyonstudiedzoologyat
228
C.A.Hoarecontributed179papersin60yearswithBurroughsWellcomeupto 1980,PapersatWI/GC/57G.MacDonald,(1980):4951.
123
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
124
234 in1907.
washyoscyamine,isolatedamongotheralkaloidsfrom DaturametelbyReynolds,Carrand
237 PymanandreleasedontothemarketinMarch1908.
234
CecilA.Hoare,CharlesMorleyFletcher(1949):627642.
235
HistoryoftheFirmofBurroughsWellcomeWestKentAdvertiser(21March 1924),WF:YLbox25D3DW.
236
T.A.Henry,(1939):6971.
238
124
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
125
BargerandCarrpreparedtheactiveprinciplesofergotincludingacomplexof
239 alkaloids,calledergotininwhichDaleassayedinanaesthetisedcats. Hisfindingsopened
240 upnewavenuesofresearchonthephysiologicalcontrolofbloodpressure. Theteamof
anothercompanyDalefoundthataminutequantitycausedstoppageofanimalhearts,and thisalarmingconsequencewasduetoanimpurity,whichEwinsidentifiedas
242 acetylcholine.
239
A.J.Ewins,Acetylcholine.ANewActivePrincipleofErgotBiochemicalJournal,8 (1914):44.
243
125
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
126
synthesise,otheramineslikeadrenaline,whichrepresentedthefirstsyntheticanalogueofa
248 naturalhumanhormone. Puresamplesoftheseaminesstimulatedanimalsheartsin 249 Dalesstudies. OverfiftychemicalderivativesweresynthesisedattheWCRLallowing
Daletogainathoroughunderstandingoftherelationshipbetweenphysiologicalactivity
250 andchemicalstructure. Theergotexamplerepresentsthemostlastingandimportant
244
G.Barger,A.J.Ewins,TheAlkaloidsofErgotIIJ.ChemicalSociety 97 (1910):284.
247
G.Barger,H.H.Dale,ChemicalStructureandSympathomimeticActionofAmines J.Physiology 41(1910):1959G.Barger,G.S.Walpole,FurtherSynthesesofp hydroxyphenylethylamineJ.ChemicalSociety (1909):1720G.Barger,G.S.Walpole, PressorPrinciplesfromPutridMeatJ.Physiology 38(1909):23,343H.King,A.J. Ewins,TheSynthesisofSomeNewDimethyltetrahydroquinolinesJ.ChemicalSociety 103(1913):104H.A.D.Jowett,J.ChemicalSociety 93(1908):563.
249 250
W.S.Feldberg,H.H.Dale(18751968):128.
126
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
127
attheWCRLwasreadilyapparentinreferencestoGermanpublicationswithinmany
255 BurroughsWellcomecompanydocuments.
G.Pearson,(1936),WF:88/24:41d:8. PymanLaboratoryNotes,(7February1906),WF:85/9Book1.
255
127
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
128
Jowett,HannandPymanpreparedaseriesofsyntheticchemicalscalledtropeinesfor
257 physiologicalstudiesbyDaleandMarshallattheWPRL. Someoftheseweremirror
256
H.A.D.Jowett,A.C.O.Hann,PreparationandPropertiesofSomeNew TropeinesJ.ChemicalSociety (1906):35765F.L.Pyman,H.A.D.Jowett, RelationshipsBetweenChemicalConstitutionandPhysiologicalActionintheTropeines J.ChemicalSociety 91(1907):92 J.ChemicalSociety 95(1909):1020F.Pyman, RelationshipBetweenChemicalConstitutionandPhysiologicalActioninCertain SubstitutedAminoalkylEstersJ.ChemicalSociety 93(1908):1793 J.ChemicalSociety 111(1917):167(onthebasisofalecturegiventotheChemicalSociety,6December 1917).
258
M.Barrowcliff,F.Tutin,TheConfigurationofTropineand[psi]Tropineandthe ResolutionofAtropineJ.ChemicalSociety 95(1909)196677F.H.Carr,W.C. Reynolds,TheSpecificRotatoryPowerofHyoscyamineandtheRelationBetweenthatof AlkaloidsandtheirSaltsJ.ChemicalSociety (1910)T1328:180H.King,The PossibilityofaNewInstanceofOpticalActivityWithoutanAsymmetricCarbonAtomJ. ChemicalSociety (1914):249.Itwasknownin1815thatsomecompoundsexhibited differentialrotationoflight.Pasteurdemonstratedthisclearlywithtartaricacidin1848. VantHofandLeBelrealisedthatitwaswithcarbonattachedto4differentgroupsE.S. th Taylor,AHistoryofIndustrialChemistry (London:Heinemann,4 edition1933):220224 H.King,TheResolutionofHyoscineanditsComponents,TropicacidandOscineJ. Chem.Soc.115(1919):476H.King,TheStereochemistryofHyoscineJ.Chemical Soc.115(1919):974.
128
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
129
whowewillmeetagainlater,hadjoinedtheexperimentallaboratoryinNovember1912
259 andhebecamemuchinvolvedinthiswork,beforehetransferredtotheWCRLin1914.
ManyexamplesexistwhereBurroughsWellcomecharacterisednaturalproductsto identifytheactiveingredientandpreparedstandardisedmedicinessuchasstrophanthus,
260 willowbarkextracts,andnovelextractsincludingApocynum,diuretics,andtyramine.
FrankTutinjoinedtheWCRLinDecember1903andexaminedthechemicalconstitution
261 ofvariouschemicallysubstitutednaturalproducts. From1908Pyman,Reynolds,
BarrowcliffandRemfry,influencedbyEhrlichssuccesswithAtoxyl,anarsenicderivative fortreatingsyphilis,preparedaseriesofsyntheticaromaticarsonicandarsinicacidswhich
262 263 werepatented. Theyanalysedironarsenatetocharacteriseit. However,onlyone
259
H.H.Dale,P.P.Laidlaw,C.T.Symons,AccelerationoftheMammalianHeartby StimulationoftheVagusNerveJ.Physiology 39(1909)Proc.xiiiP.P.Laidlaw,An ActivePrincipleofApocynumCannabicumJ.Physiology 38(1909):76P.P.Laidlaw, H.H.Dale,TheActionofanActivePrinciplefromApocynumHeart1(1909):138H. H.Dale,P.P.Laidlaw,ThePhysiologicalActionofbetaIminazolylethylamineJ. Physiology 41(1910):318344H.H.Dale,P.P.Laidlaw,ThePresenceinErgotand PhysicalActivityofbetaIminazolylethylamine J.Physiology 40(1909)Proc.xxxviiiH. H.Dale,P.P.Laidlaw(18811940)ObituaryNoticesofRoyalSocietyofLondon 3 (1941):444P.P.Laidlaw,H.H.Dale,TheActionofSomeDiureticsProceedingsof theRoyalSocietyofMedicine3(1909)TherapeuticPharmacologysection:38.
261
129
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
130
couldnotcompetedirectlyonamanufacturingcapacitywiththeGermanfirmsin producingsyntheticdrugs,buttheycreatedtheirownmarketnichewiththeirpurifiedand standardiseddrugs. 3.6Conclusions:TheImpactoftheLaboratories. IntheperiodcominguptotheFirstWorldWar,BurroughsWellcomewasa diversifyingpharmaceuticalcompany.Notonlydidtheyproducetheoriginalsuccessful Wyethbrands,inorganicdrugsandalkaloidalextracts,buttheyalsoproducednovel chemicalcompoundsandnonsterilesera,whichwerecontrolledforstrengthandpurity. ThisbecameincreasinglyimportantandDowsonwasbothblamedandsackedonan occasionwhenheallowedpoorlystandardisedbiologicalmedicinesontotheAmerican
265 market,leadingtoDalebecomingheadoftheWPRL. DalerecalledthatGlennywas 266 makingthebestthathecouldofwhatheknewnottobereallysuitableconditions.
Processing,labellingandbottlingweremovedtoanewbuilding,speciallydesignedand constructedandwithventilationbysterileair,andwithGlennyastheHeadofthe
267 Immunologydepartment.
264
Dalewasofferedatemporarypostat800p.a.increasedto1,000whenhebecame Director.Incomparisonauniversitylecturerreceivedaround600:DaleArchives93HD 143.8W.S.Feldberg,H.H.Dale18751968(1970):79174F.B.PowertoHenry Wellcome,(31January1902),WF:88/9428aE.M.Tansey,(1989):1116E.M. Tansey,WhatsinaName?HenryDaleandAdrenalineMedicalHistory 39.4(October 1995):45976H.O.Schild,DaleandtheDevelopmentofPharmacologyBr.J. Pharmacology (February1997),120(4Suppl):5048Obituary,DrW.C.FowlerBritish MedicalJournal (24June1967):84647.
266
130
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
131
Pharmacopoeias,emphasisingtheneedforbiologicalstandardsandassayofactive principlesratherthantotalalkaloids.Allethicalmanufacturersaimedtodifferentiatetheir
271 productsfromthosewithlesserstandards. SeveralfirmscontributedtotheCodexandto 272 themedicalliteratureondrugpurity. Theemphasisonpurityandstandardsrecognised
268
BritishPharmaceuticalCodex,commentsandreportsbyF.B.Powerandothers, WI/GC/5Acc35.
271
131
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
132
medical journalswouldnotallowreprintsofpublishedpaperstobeusedaspromotional
275 items.
Druggist67(30September1905):348 ThePurityofPharmaceuticalChemicalswith SuggestionsforCommerciallyObtainableStandardsChemist&Druggist72(23May 1908):7927B.P.ArsenicTest,Chemist&Druggist81(29July1912):122123T. TustingCocking,TheContaminationofZincanditsCompoundswithLeadChemist& Druggist69(29September1906):507PharmaceuticalChemicalStandardsChemist& Druggist85.1(4July1914):4955TheBritishPharmaceuticalCodex:anImperial DispensatoryfortheuseofMedicalPractitionersandPharmacists,PharmaceuticalSociety ofGreatBritainLancet (2November1907):982.
273
TheUnificationofOfficialFormula'sforPotentMedicamentsLancet(23February 1907):527andLancet(27April1907):1178.
274 275
JohnP.Swann,(1988):3134.
P.W.J.Bartrip,MirrorofMedicine:aHistoryoftheBritishMedicalJournal (Oxford:BritishMedicalJournal:ClarendonPress,1990).
132
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
133
standardsfortheirpreparedproprietaryproductsandoneoftheiranalysts,E.F.Harrison,
277 contributedsignificantlytothecampaignsoftheBritishMedicalJournal.
276
133
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
134
Dalerecalledtenyearslatertherewassomethingofapioneeringcharacterin thosedaysinthiscreationoflaboratorieswithseriousresearchinview,inconnectionwith
280 aBritishpharmaceuticalbusiness.
establishingWellcomesresearchlaboratoriesthatmanyofthekeyresearchersweresought tojointhenewlyformedMedicalResearchCommittee,ofwhichmoreinthenext
282 chapter. LaidlawleftBurroughsWellcomein1913fortheSirWilliamDunnlectureship
inPathologyatGuysHospitalandcontinuedhisworkonergotinhisnewroleandfrom1 January1914,heandDalebegantestingthepotencyofposteriorpituitarylobeextractsas
283 wellasamides,alkaloids,andfurtherextractsofergotanddigitalis.
280 281
W.S.Feldberg,HenryHallettDale18751968(1970):92.
134
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
135
notablyfromCambridge.Hopkinsformerstudent,PatrickP.Laidlawbasedatthe
284 physiological laboratoryofGuysHospital,wasattractedtojoinDale.
InsummaryBurroughsWellcomedidnotattempttocompetewithGermanyinthe largescalemanufactureofsyntheticdrugsthoughtheywereabletoproducesomeofthese, atleastonasmallscale.ThelargerGermanfirmsbasedtheirsyntheticdrugsonthereadily availablewastematerialsfromthedyeindustry,whereasBurroughsWellcomeandGerman pharmacybasedpharmaceuticalmanufacturerssuchasMerckconcentratedonplant extracts.InBritaintherewasnotsuchareadysupplyof manufacturingchemistsand chemicalengineerstoproducedrugsefficientlyonalargescale,butthemaincommercial disadvantagewasthatthescaleofchemicalproductionatBurroughsWellcomeremained smallincomparisontothedyefirms. Ihaveshownthatconsiderablechemicalexpertisewasdevelopedinproducing syntheticalkaloidsonasmallscalesothatextractscouldbestandardisedagainsttheir activeingredientsinordertoproducereliableactivity.ThestrengthsofBurroughs Wellcomewerechemicalcharacterisation,smallscalechemicalsynthesis,biological standardisationandtheproductionofTabloidsorothernoveldosageforms.Thegrowing expertiseinchemistryandlargescalemanufacture,however,enabledthemtosorapidly manufactureSalvarsanandothercomplexsyntheticdrugswhenthewarbrokeout. In1913HenryWellcomeconsolidatedallofhislaboratoriesunderoneumbrella, creatingtheWellcomeBureauforScientificResearch(WBSR)underBalfour,leaving WenyonasDirectorofResearchintheTropics.WalterM.FletcheroftheMRChad concernsaboutfirmssupportingresearchwheretheycouldinfluencepublishingofresults asfirmsaretiedhousesbuthesuggestedthattheapparentfreedomconferredbythe
284
Laidlaw,previouslyDunnProfessorofPathologyatGuyshospitaltookupa permanentpostattheN.I.M.R.ataninitialsalaryof750p.a.:MRCAnnualReports 19141920:MRCCommitteeMinutesII,(16December,1921):167H.H.Dale,P.P. LaidlawBiographicalMemoirsofFellowsoftheRoyalSociety (1941):427447.Laidlaw didworkonhistidineandtoxinsP.Laidlaw,A.Glenny,DetectionandConcentrationof AntigensbyUltrafiltration,PressureDialysisetc.withSpecialReferencetoDiphtheriaand TetanusToxins:BiochemicalJournal 9(1910):298TheCambridgeconnectionincluded Mellanby,Barger,Dale,Laidlaw,Burn,Dowson,KanthackH.H.Dale,PatrickPlayfair Laidlaw,18811940ObituaryNoticesofFellowsoftheRoyalSociety 3(1941):427447.
135
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
136
placedatthedisposaloftheWarOffice,offeringtrainingandsupportonTropical
286 Research. HenryWellcomemaintainedaninterestinTropicalMedicinethroughouthis
285
MaisieFletcher,TheBrightCountenance:aPersonalBiographyofWalterMorley Fletcher(London:Hodder&Stoughton,1957):187.
286
CecilA.Hoare,CharlesMorleyWenyon18781948(1949):62742.
136
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
137
CHAPTERFOUR WarandtheEstablishmentofaBritishSyntheticDrugIndustry Wecannotrecoverwhatwehaveneverhad...theproductionoffine 1 chemicalshavefromthefirstbeenaGermanindustry. 4.1Introduction:theRelianceonGermanDrugsandChemicals. ChapterTwoshowedthatBritainreliedonGermanyforsyntheticdrugs,chemical intermediatesandcertainalkaloids.TheRoyalCommissiononVivisection,whichreported in1912,listedthedrugsthathadrecentlybeenintroducedasaresultofanimalstudiesand mostwerefromGermany:thesoporifics,chloral,sulphonalandveronallocalanaesthetics, cocaine,eucaineandstovaintheanalgesicsandantipyretics,antipyrine,antifebrin, phenacetinandexalginphysostigmine(oreserin)forglaucomaamylnitritesforangina
2 andthediuretics,caffeine,theobromine,diuretinandurotropine.
andChemist&DruggistthatGermansyntheticdrugsheldadominantpositioninthe
4 Britishmarket. Furthermore,becausetheuseofGermantradenameswasfrownedupon,
F.H.Carr,RecoveryofTradeLosttoGermanyChemist&Druggist85.2(29 August1914):51. 2 FinalReportoftheRoyalCommissiononVivisectionBritishMedical Journal (16 March1912):62627. 3 Thesewereacetylsalicylicacid(Aspirin),barbitone(Veronal),benzaminelactate( Eucainelactate),chloralformamide,dicimorphinehydrochloride(Heroin),hexamine (Urotropine),phenolphthalein(Purgen)British MedicalJournal (17October1914):672 73 BritishPharmacopoeia1914(London:Constable&Co,1914)TheBritish PharmacopoeiaChemist&Druggist85.2(3October1914):4958TheBritish Pharmacopoeia1914PharmaceuticalJournal (3October1914):45255. 4 SyntheticMedicinalChemicalsBritishMedicalJournal (23January1915):168169 MedicalNewsReplybyBurroughsWellcomeBritishMedicalJournal (6February 1915):257.
137
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
138
Britishdoctorsoftenuseddrugs,distributedbywholesalers,notevenrealisingthatthey
5 wereGerman.
ForexampleJohnBelldistributedMarlesenforBayer.BritishMedicalJournal (5 September1914):55. 6 DrugsandMedicinalPreparationsChemist&Druggist85.2(3October1914):34. 7 D.L.Howard,British&ColonialPharmacist (August1926):243. 8 BurroughsWellcomeletter.Chemist&Druggist85.1(22August1914):46B. Dott,VegetableAlkaloidsHowtheWarhasAffectedProductionChemist&Druggist 88.4(29July1916):777T.A.Henry,ThePlantAlkaloids(London:J.&A.Churchill,3rd edition,1939)R.Robinson,J.ChemicalSociety 111(1917):876. 9 JudySlinn,AHistoryofMay&Baker18341984(Cambridge:Hobsons,1984): 4445. 10 BoardofTradeNotesChemist&Druggist85.2.(5September1914):40F.H. Carr,presscuttingsin2131B/CARR2No.143,ImperialInstitute(5September1914):1 D.Bolton,TheDevelopmentofAlkaloidManufactureinEdinburgh18321939
138
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
139
11 apomorphine,aconite,colchicines,cotarnum,homatropine,hydrazolineandspaline.
Therewereshortagesofformamine(hexamine),quinineandsanatogen,andthese
12 amountedtoover1m.worthofsyntheticdrugs.
difficulttoproducethesalicylateshere.EvensimplesyntheticssuchasAspirinwerenot manufacturedcommerciallyinBritainbecauseitcouldnotbemanufactured:atprices
14 whichcouldcompetewiththoseatwhichGermanywasabletoofferthem.
Germanfirmscreatedaseriesoftrustsandcartelstomaintainmonopoliesand
15 discouragecountermeasures. Thus,thelackofcompetitivenesswasalsodueto:
Chemistry&Industry (1976):701708LondonPharmaceuticalIndustryChemistry& Industry (1933):667698. 11 T.A.Henry,(1939). 12 F.H.Carr,SyntheticOrganicDrugs:theirManufactureasAffectedbytheWar Chemist&Druggist(29July1916):7789. 13 ManufactureofAntipyrinChemist&Druggist 85.1(15August1914). 14 Acartelexistedforiodineandotherdrugs.TheWarandtheScarcityofSome DrugsBritishMedicalJournal (27March1915):55961. 15 L.F.Haber,TheChemicalIndustry19001930:InternationalGrowthand TechnologicalChange(Oxford:ClarendonPress,1971):110,118,2756. 16 F.H.Carr,textofhis1926SCIspeech,ManufactureofOrganicMedicinal ChemicalsinhisArchivesatImperialCollege.B/CARR/IIILectures192060.
139
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
140
Internationaltradingisnotonareciprocalbasis...foreignchemicalsand pharmaceuticalpreparationsareadmittedintothiscountry,practicallyduty freewhilstgoodsexportedfromthiscountrytocountriesabroadaresubject toanexceedinglyhigh'advalorem'duty.Onevastcountry (America)... directlyprohibitstheimportofpharmaceuticalpreparationsofother countrieswhileotherimmensestatesdosoindirectlybymeansof(the)high 17 duty. ThroughoutthenineteenthcenturyBritainhadmaintainedafreetradepolicyinmarked contrasttoincreasingprotectionisminFrance,Italy,theUnitedStates,NewZealandand
18 Canada.Allen&HanburysfoundthisparticularlycostlyinAustralia. Americantariff
protectionhadeffectivelykilledoffBritishalkaliexportsandnowprohibitedimportationof
19 somepharmaceuticalsandcontrolledadvertisingtophysicians.
InthischapterIwillexaminehowBritainreactedtothelossofGermandrugsatthe outbreakofthewar.Iexaminethecollaborationsestablishedtodeterminewhichdrugswere essentialandhowthesecouldbemadeorreplaced,andhowtheshockoftheWarbrought hometheneedforfirmstocollaboratetomakethebestuseofresources.Thischapterwill showhowtheprewareffortsofBurroughsWellcomedescribedinchapter3formeda valuabletechnicalbaseforthepreparationandanalysisofnewdrugs,bothinternallythrough theirexperiencedstaffsuchasPymanandJowett,andexternallythroughHenryDaleand ArthurEwins,whojoinedtheMedicalResearchCommittee(MRC)andarrangedstudiesby theirSalvarsanCommitteetoshowthatBritish produceddrugswereassafeastheGerman versions.Thesestudieswerethefoundationforfurtherdevelopmentsinbiological standardisationofdrugsandofclinicaltrials.FrancisCarr,ArthurEwinsandothersspreadthe BurroughsWellcomemodelofchemicalresearchanddevelopmentandlargescale manufacturingtootherpharmaceuticalfirms.Finally,Iwillexaminesomeofthecollaborations thatestablishedtheBritishpharmaceuticalindustryonamoresecurefooting.
17 18
BritishChemicalIndustriesBritishMedicalJournal (5March1921):347. L.F.Haber,(1971):239BritishDyestuffsChemist&Druggist94.2(8October 1921):39D.ChapmanHustonandE.C.Cripps,ThroughaCityArchway:TheStoryof Allen&Hanburys17151954(London:JohnMurray,1954):245. 19 W.J.Reader,ImperialChemicalIndustriesLtd.AHistory:TheForerunners1870 1926volume1(London:OxfordUniversityPress,1970):169B.E.ReubenandM.L. Burstill,AGuidetotheTechnologyandEconomicsoftheChemicalIndustry (London: Longman,1973)J.Bishop,DrugEvaluationProgramsoftheA.M.A.190566Journalof theAmericanMedicalAssociation 196(1966):496.
140
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
141
4.2GovernmentResponsestotheConditionsofWarandDrugShortages TheoutbreakofWarledtoamassivedemandfordyestomakeuniforms,anddrugs,
20 especiallyantiseptics,anaesthetics,painkillersandantitoxins. Manyofthesame
managethissituation.Theyhadtoensurethatnoessentialmaterialswereexported,and theyhadtofindalternativesourcesofGermandrugs,chemicalintermediatesandraw
22 materials.LongertermsolutionsincludedgrowingsomemedicinalplantsinBritain or
importingdrugsfromalliedcountries,butthereweremanyurgentrequirements.
th InpassingtheTradingwiththeEnemyActofAugust5 1914(undersection8of
theCustomsandInlandRevenueAct),theGovernmentimmediatelyspecifiedalistof essentialchemicalsincludingdrugs,whichcouldnottobeexportedtothecontinent withoutaspeciallicence:glycerine,lead,saltpetre,nitrateofsodium,carbolicacid,ethyl andmethylalcohols,alkaliiodides,belladonnaanditspreparationsandalkaloids,bismuth anditssalts,boricacid,bromineandalkalbromides,castoroil,chloroform,cinchona, quinineandsalts,cocapreparations,andalkaloids,colloidin,corrosivesublimate,cresol andpreparations,nitrocresol,digitalis,ether,ethylchloride,formicaldehyde,henbaneand preparations,iodineandpreparations,Lysol,mercuryandsalts,morphiaandother alkaloidsofopium,nuxvomicaandalkaloids,paraffin,protargol,salicylicacid,Salvarsan andallfinechemicals. CertificatesoforiginwererequiredforNorway,Sweden,Denmark,ItalyandThe
23 Netherlands. Beforeanexportlicencewasgranted,applicantshadtospecifythenature
20
797.
21
36.
22
141
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
142
andquantityorweightandvalueofgoods,whereitwasgoingandwhy,andwhichports
24 andshipswouldbeused. TheArmyimmediatelyrequisitionedallquinine,phenacetin, 25 andformaldehydeproduced,aswellasseveralchemicalintermediates. TheGermans
immediatelyreciprocated,banningexportstoBritainofchemicalsrequiredformaking
26 munitions,dyestuffsanddrugs. Thismadeabadsituationevenworse.Forexample,
BritainhadreliedonGermanyforphenol,useditselfasanantiseptic,butalsoneededfor
27 theproductionofdrugssuchasAspirinandPhenacetin.
TheGermansdidnotbelieveitwaspossibleforBritishfirmstoproducesynthetic drugsonacommercialscale.PerkinquotedaseniorfigurewithintheGerman Chemical Industry,probablyDuisbergofBayerasstating: Englandtalksnotonlyofholdingherowninthewar,butofbeatingusin thechemicalindustry.Shecannotdoit,becausethenationisincapableofthemoral efforttotakeupsuchanindustry,whichimpliesstudy,concentration,patience,and 28 fixingtheeyeondistantconsequences,andnotmerelyonthemonetaryresult. Britishdrugfirmshadreliedonthedyeindustryforchemicalintermediatesbuteventhe largerBritishdyefirmssuch asClaytons,ReadHollidayandLevinsteinsreliedonimports
29 fromGermanyofchemicalintermediatessuchasbenzene,toluene,andcarbolicacid. 30 Britishfirmsweremuddlingthrough. Therawmaterialsupplyofinorganicchemicals
suchasbromides(usedforepilepsy)andpotashfrommineraldepositsinGermanywas immediatelycompromisedbytheWar,butatleasttherewerealternativesourcesinSouth
31 32 America. HoweversuppliesallovertheworldwerecorneredbyGermany.
1914):33TradingwiththeEnemyProclamationChemist&Druggist85.2(12 September1914):34AbsolutealcoholChemist&Druggist(19September1914):48. 24 ProclamationonExportationofMedicinesChemist&Druggist 85.2(3October 1914):335. 25 MedicalNewsBritishMedicalJournal (5May1917):603. 26 F.H.Carr,SyntheticOrganicDrugs:theirManufactureasAffectedbytheWar Chemist&Druggist87(29July1916):778779. 27 TradePriortotheWarChemistandDruggist85.1(15August1914):48W.J. Reader,MinistryofMunitions(1970):2501,2867. 28 QuotedbyW.H.PerkininW.M.Gardner,(1915):407427quoteonp.415. 29 L.F.Haber,(1971):121,148. 30 W.J.Reader,(1970):267. 31 B.Dott,VegetableAlkaloids:HowtheWarhasAffectedProductionandF.H. Carr,TheManufactureofDrugsAffectedbytheWarfrom BritishandColonial Pharmacist(June1915):4367.AcopyofthispaperisintheArchivesofFrancisH.Carr:
142
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essentialintermediatesfromdyemakerswereamidophenols,dimethylalanine, dimethylsulphide,betanaphthol,andphthallicanhydride. SomeBritishcompanieshadmadeeffortsincaseofwartoavoidshortages.Sir EdwardEvansofEvansSons,Lescher&WebbhadattendedtheBritishPharmaceutical CongressasPresidentin1912inwhichthegeneraltopicofdrugtradeinwarwas discussed.HisfirmboughtupsuppliesofGermandrugsfromSpainandPortugalthey cultivatedherbsandplannedincreasedeffortstomakedigitalis,henbane,colchicum, olearin,belladonna,peppermint,lungwortandaromatics.BurroughsWellcome,likemost otherswereillpreparedforthesuddenoutbreakofwar. Insummarythewarbroughtanimmediateshortageofsomenaturalplants, inorganicdrugs,alkaloidsandbiologicalsandanabsolutelackofGermansyntheticdrugs. Thefirststrategyadoptedwastoseekalternativesourcesoralternativedrugs.Thesecond wastotrytomaketheGermandrugs.Althoughsomeshortageswereimmediately obvious,therewerealsomoresubtlerequirementsforchemicalintermediates,someof whichwerenotimmediatelyrecognised.
B.CARR2130B/CARR:3atImperialCollege,LondonTheWarandtheScarcityof SomeDrugsChemist&Druggist85.2(5September1914):4BoardofTradeReturns to31AugustBritishMedicalJournal (3September1914):47. 32 C.A.Hill,T.D.Morson,ManufactureofFineChemicalinRelationtoBritish ChemicalIndustryfrom BritishandColonialPharmacist(June1915):4367.Acopyof thispaperisintheArchivesofFrancisH.Carr:B.CARR2130B/CARR:3atImperial College,London. 33 F.H.Carr,TheWarandBritishProductionofFineChemicals,SyntheticOrganic DrugsandAlkaloidsBritish&ColonialPharmacist(June1916):4367in2130B.CARR PresscuttingsIV.
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34 andthiswaspoorlyunderstooduntilMoultonbegancollatingdata. Fortunately,the
PharmacopoeiaCommissionhadjustcompletedworkonthenewPharmacopoeia,which
35 wasduetobepublishedinDecember1914. TheCommissiononPatentMedicines,which
metbetweenMay1912andJune1913,alsoreportedjustbeforetheoutbreakofWar. Theirextensivereportof782pagesincludedmanyrecommendationstoover14,000
36 37 questions. TherehadalsobeenarecentProprietaryMedicinesInquiry. Togetherwith
theBritishPharmaceuticalCodexof1907,theseformedagoodbasisfordefiningessential
38 drugs. PreparationofthePharmacopoeiaandCodexhadincludedpharmaceutical
39 industryinput. ThenextstepwastocheckwhichdrugscouldbemadeinBritain,what
A.J.P.Taylor,EnglishHistory19141945(Oxford:Clarendon,1988):45. TheBritishPharmacopoeia(1914). 36 AHugeRevenueThreatenedBritishMedicalJournal (11May1912):1090. PatentMedicineCommitteeChemist&Druggist85.1(24October1914):47. 37 ProprietaryMedicineInquiryPharmaceuticalJournal 93(8August1914):218. 38 TheBritishPharmaceuticalCodexLancet (22November1907):1247. 39 TheBritishPharmacopoeiaBritishMedicalJournal (13August1914):8845 TheBritishPharmacopoeia1914BritishMedicalJournal (3October1914):4958.It cameintoforceon31December1914. 40 F.H.Carr,SyntheticOrganicChemicalIndustryNottinghamJournal (October 1918)ChairmansaddressbyF.H.CarrtotheNottinghambranchoftheSCI.CopyinF. H.CarrarchivesatImperialCollege.B/CARR/IIILectures192060.
144
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
145
41
145
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
146
GeorgeGreenatLeedsUniversity,whohadbeenassociatedwiththedyestuffsfirms,
46 Brooke,SimpsonandSpillerandwithClaytonAniline andRaphaelMeldola,FRS, 47 ProfessorofChemistryattheRoyalCollegeofChemistry,thenatFinsburyPark. The 48 49 representativesof dyestuffsincludedHerbertLevinstein ofLevinsteins:JosephTurner,
chairmanofReadHollidayofHuddersfield,andMiltonS.SharpoftheBradfordDyers
50 Association. Italsoincludedtwopharmaceuticalmanufacturers,DavidL.Howard,head
Thecommitteequicklyorganisedincreasedsuppliesofsulphuricandnitricacids,liquid
52 chlorine,syntheticbenzolandphenol,toincreasedrugproduction.
Itbecameimperativetodefineexactlywhichdrugswereessentialandwhat constitutedareasonablealternative.Itwasclearthatanaesthetics,painkillersand
45 46
M.R.Fox,(1987):92 Chemistry&Industry (1929)7:1009. J.Baddiley,ArthurGeorgeGreenObituaryNoticesofFellowsoftheRoyal SocietyofMedicine4(1943):25170. 47 ForbackgroundseeAlexanderFindlayandWilliamHobsonMills(eds.),British Chemists(London:TheChemicalSociety,1947):96,1767,2478W.J.Reader,(1970): 278L.F.Haber,(1971):3535M.Hainsworth,WhowasRaphaelMeldola?Biologist 39(1992):72ObituaryofRaphaelMeldolaProc.Roy.Soc.Lond.93(1917):2937. 48 HerbertLevinstein,J.Soc.Chem.Ind. Jubileeedition(1931):92. 49 M.R.Fox,(1987):4243. 50 M.R.Fox,(1987):7692. 51 ThecommitteealsoincludedGeorgeBeilbyJP,F.R.S.,apastpresidentofthe S.C.I.,MaxMusprattofthePatentOffice,SirArthurTedderofCustoms&Excise (ChemistryandPharmaceuticals)andProf.JamesJohnstonDobbie,F.R.S. BritishMedical Journal (5September,1914):40W.J.Reader.(1970):26670W.H.PerkininW.M. Gardner.(1915):345,407,419. 52 F.H.Carr,TheManufactureofSyntheticOrganicDrugsAffectedbytheWar, BritishandColonialPharmacist(June1915)4367,(quote)in2130B/CARRcuttingsIV: 3,ArchivesatImperialCollege.
146
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
147
increasedinterestinensuringthatthemostappropriatedrugswereprescribed.
54 SirRobertMorant, acivilservantpreviouslyattheBoardofEducation,became
chairmanoftheNationalHealthInsuranceCommissionandsetuptwoadvisory committees.TheCommitteeonDrugSupplydecidedwhichspecificdrugsweremost
55 needed itsmembersincludedthePresidentofthePharmaceuticalSociety,MrEdmund
White,theVicePresident,MrE.T.Neathercott,56 andtheSecretary,MrW.J.U.
57 Woolcock,whowasemployedattheWarOffice. JohnC.UmneyofthePharmaceutical
53
S.W.F.Holloway,RoyalPharmaceuticalSocietyofGreatBritain18411991.A PoliticalandSocialHistory (London:ThePharmaceuticalPress,1991):52,32440. 54 SirRobertMorantwasnamedasthefirstCommissioneroftheNHIon28 November1911:S.W.F.Holloway,(1991):338foralifehistoryofMorantseeD.Cox Maksimov,TheMakingoftheClinicalTrialinBritain,19101945.Expertise,theState andthePublic(Cambridge:PhD,September1997):9097. 55 MembersofthecommitteeincludedtheNHICommissionerMrJackSmith Whitaker,aschairmanSirThomasBarlowBartSirThomasLauderBruntonBartDr.A. Cox,MedicalSocietyofBMAProf.A.R.Cushny,ProfessorofPharmacologyat UniversityCollege,LondonDr.E.RowlandFothergill,CouncilofBMADr.B.A. Richard,SecretaryofLondonPanelCommissionDr.F.J.SmithDr.WilliamHaleWhite PresidentoftheRoyalCollegeofPhysiciansDr.E.W.Adams,medicalofficer,NHI CommitteeonDrugSupplyChemist&Druggist85.1(22August1914):33and(29 August1914):59and(5September1914):4042. 56 PharmaceuticalSocietyofGreatBritainChemist&Druggist99.1(28July1923): 117E.T.NeathercottwasPresidentofthePharmaceuticalSociety192024,S.W.F. Holloway,(1991). 57 WilliamJamesUglowWoolcockwasoneoftwopharmacistsrepresentedonthe firstNationalAdvisoryCommitteeonInsurancecreatedaftertheNationalInsuranceActof 1911.HewasappointedasLocalAssociationsOfficerandfrom1913wasSecretaryand registrarofthePharmaceuticalSociety,untilhisappointmentasGeneralmanagerofthe AssociationoftheBritishChemicalManufacturersformedin1916.InDecember1918he wasreturnedasCoalitionLiberalM.P.forCentralHackney:S.W.F.Holloway,(1991): 337,339,355,392.
147
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
148
SocietyandCharlesA.HillofBritishDrugHouses,whohadbeeninvolvedinproduction
58 ofboththe1898and1914Pharmacopoeia,werealsomembers.
Inparallel,representativesoftheLondonChamberofCommerceincluding
59 Pharmaceuticalmanufacturers,metwithJohnAnderson(laterViscountWaverley) ofthe
NationalHealthInsuranceCommissionandSirRobertMoranttoestablishthesecond committeeasanEmergencyCommitteeofTradeSectionto considerandadviseusastothebestmeansofobtainingfortheuseof Britishindustries,sufficientsuppliesofchemicalproducts,coloursand dyestuffsofkindshithertolargelyimportedfromcountrieswithwhichweare 60 presentlyatwar. JohnAndersonwasoneofthefewseniorofficialswhounderstoodchemistry, havingreadscienceinScotlandandGermanybeforejoiningthecivilservicehebecame instrumentalindirectingBritishfirmstoproducesyntheticdrugs. JohnC.UmneyofthePharmaceuticalSociety(whowasalsoontheCommitteeon DrugSupply)chairedthisEmergencyCommitteeofTrade,whichincludedthe pharmaceuticalmanufacturersDavidLloydHowardofHowards,CharlesA.HillofBritish
61 DrugHouses,T.D.Morson,ThomasTyrer,withT.E.Lescher, andE.A.Webbofthe
58
J.C.UmneywasaBoardmemberofthefirmWright,LaymanandUmney PharmaceuticalJournal (22August1914):294JohnCharlesUmney,Publicationofthe PharmacopoeiaChemist&Druggist83.2(26July1913):53Obituary,CharlesUmney Chemist&Druggist88.5(25November1916). 59 LordBridges,JohnAnderson,ViscountWaverleyBiographicalMemoirsof FellowsoftheRoyalSociety 4(1958):307325. 60 ExportationofMedicinesChemist&Druggist85.2(19September1914):33for backgroundseeMajorGeneralSirW.G.MacPherson. HistoryoftheGreatWarVolume 1.(LondonH.M.S.O.,1921):178179.
61
148
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
149
62 stillhadtobegtheWarOfficeforsuppliesofsulphuricandnitricacids. Atthestartofthe
establishedin1913,andwastoplayanimportantrole,particularlyrelatingtotheassayof
64 newly producedSalvarsanaswillbedescribedlaterinthischapter.
62 63
C.A.Hill,T.D.Morson,TheBritish&ColonialPharmacist(June1915):4367. MaisieFletcher,TheBrightCountenance:aPersonalBiographyofSirWalter MorleyFletcher (London:Hodder&Stoughton,1957):128T.R.Elliott,WalterMorley Fletcher(18731933)ObituaryNoticesofFellowsoftheRoyalSocietyofMedicine (1934)I:153163. 64 LindaBryder,TuberculosisandtheMRCinJoanAustokerandLindaBryder (eds.),HistoricalPerspectivesontheRoleoftheMRC (Oxford:OxfordUniversityPress, 1989):121. 65 BoardofTradeNoticesTheManufactureofSalvarsanChemist&Druggist85.2 (5September1914):40.
149
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
150
formanufactureas,forexample,glasswareforperformingreactionswasalsoinshort
66 supply.
Alcoholsupplieswereimprovedfurtherbythemergeroftheprincipalwhiskydistillersto formtheDistillersCo.Ltd,withasubsidiaryBritishIndustrialSolventsmakingacetoneat
68 Hull.
uponGermanyandcalledupontheGovernmentforassistancewereUniversitychemistry professorswhoconsultedwidelyforthedyefirms,andweremembersoftheSocietyofthe
70 71 ChemicalIndustry. SirWilliamTilden wasalsoamemberoftheCounciloftheInstitute
ofChemistryandtheSocietyofPublicAnalysts.Hehadwarnedsincethe1880saboutthe
72 potentialconsequencesofaweakBritishchemicalindustry. Justweeksbeforethewar
66
TheLaboratoryAgentsCommitteeincludedR.Meldola,C.A.Hill,DavidHoward, H.A.D.Jowett,J.T.Hewitt,Sir.WilliamTildenandEdmundWhitewhiletheGlassware committeeincludedMeldola,Tilden,andProfessorH.B.BakerBritishSalicylicAcid Chemist&Druggist85.2(3October1914):35. 67 RobertsonwasmadeFRSin1917andChiefGovernmentChemistin1921:R.C. Farmer,RobertRobertsonObituaryNoticesofFellowsoftheRoyalSociety 6(1949): 53961S.Miall,(1931):3856. 68 S.Miall,(1931):110. 69 AnOpeningforBritishManufacturersPharmaceuticalJournal 93(22August 1914):292. 70 ArthurMarwick,TheDeluge:BritishSocietyandtheFirstWorldWar(Boston LittleBrown,1965)A.FindlayandWilliamHobsonMills(eds.),(1947). 71 In1912hewasProf.ofAppliedChemistry,RoyalCollegeofScience,1913Chairof ChemistryatFinsburyTechnicalCollegeandin1919becameMasonProfessorof Chemistry,Birmingham:Minerva8(1970):406. 72 ForaseriesofarticlesonthisseeW.M.Gardner,(1915).
150
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
151
TildengaveaseriesoflecturesasProfessorofChemistryattheRoyalCollegeofScience,
73 TheProgressofScientificChemistryinourOwnTimes andon14August1914he
wrotetoTheTimes: ProbablytheBritishpublicisnotawarethatnearlyallthesocalled syntheticdrugsaremadeinGermany....andtoaconsiderableextentalsothe alkaloidsquinine,morphine,eucaine,etc.[British]manufacturerswillnot failtotakeadvantageoftheirpositionstopreventafamineinthese necessarymedicalmaterials.Indoingsothereseemsnosufficientreason whythemanufactureofthesesubstancescannotbeperformedhereforthe 74 benefitofourselvesandourdependencies. InhisaddresstotheRoyalSocietyofArtson27November1914onTheSupplyof ChemicalstoGreatBritainandherDependencies,heaskedthattheprotectionalready promisedtothedyeindustry,intheformofdefinitefinancialaidfromtheGovernment, shouldbeextendedtofinechemicals,andchemicalintermediatesandheexplainedthat: Theestablishmentofwhatwillbeapracticallynewindustryinthiscountry willrequireconsiderationandassistancefromtheStateifitistosurvivethe 75 periodfiercecompetition,whichwillfollowtheconclusionofthewar. TildendescribedhowBritishfirmsmightproducesomeofthealkaloidsand syntheticdrugs,hithertoonlycommerciallyavailablefromGermany.Theycouldnotyetdo soonacostefficientbasisandwouldcertainlynotbeabletocompetewithGermanyafter theWar.TheGermansmight: keepanymarketstheycanretainoutsidetheBritishEmpire,buteveryman whocaresforhiscountrywillsurelydemandthatbusinessathomeshallbe limitedtoBritishgoods.Existingconditionsofferagreatopportunitytothe BritishDrugManufacturingtrade:itwouldbenotonlyprofitablebutalso patriotictotakeadvantageofit.Thereisnoreasonwhythemajorityatleast ofthesyntheticdrugsmostgenerallyusedshouldnotbemanufacturedinthis countryifthenecessaryenterpriseandcapitalbeforthcoming.Thehome 76 demandwouldatoncebeveryconsiderable. TildendescribedtheorganisationofGermancompanies,wheremanagementwasby competentspecialists,whowereconstantlyonthelookoutfornewdiscoveriesandwho
73
151
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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TheGovernmentintroducedthePatents,DesignsandTradeMarks(Temporary Rules)Act1914amendment,whichallowedfortheweeklynotificationinTradeMark
81 th JournalsofthenamesofGermandrugsthathadbeensuspended. From8 September
77
78
F.H.Carr,(29July1916):77880L.F.Haber,(1971):129. SirJamesIrvineandJ.L.Simonson,GeorgeGeraldHenderson(18621942) ObituaryNoticesofFellowsoftheRoyalSociety 4:490.HendersonwasProfessorof ChemistryattheGlasgowandWestofScotlandTechnicalCollegeandwasPresidentof theSocietyoftheChemicalIndustry191518. 79 Prof.G.G.Henderson,BritishChemicalIndustryandtheWarPharmaceutical Journal 93(7November1914):615. 80 F.M.Perkin,inW.M.Gardner,(1915):298314. 81 TradeMarksofAlienEnemiesChemist&Druggist85.2(19September1914):52 MrD.B.Dott,AlkaloidsTheBritishandColonialPharmacist(June1916):4367. 82 GermanPatentsinBritainPharmaceuticalJournal 93(15August1914):246 Patents,DesignsandTradeMarksAct,1914PharmaceuticalJournal 93(29August 1914):31921GermanChemicalPatentsPharmaceuticalJournal 93(19September 1914):4068ThePatentsandTradeMarksofAlienEnemiesPharmaceuticalJournal 9 (26September1914):419GermanPatentsandTradeMarksPharmaceuticalJournal 93 (26September1914):436German PatentsandTradeMarksSalvarsanPharmaceutical
152
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
153
hexamine,includingUrodonal,andUrotropineweresaidtosteriliseacidurineandbenefit rheumatismandgout.Suspensionofthepatentsencouragedmanufactureby Britishfirms. LongertermpromisesofsupportingBritishmanufacturerscamefromRuncimanin1915: TheActpassedlastautumnasanemergencymeasureprovidedthatthe operatorsofGermanpatentsinthiscountryshouldhaveafullchanceof conductingthemunderlicenseanditwastheintentionoftheGovernment nottocripplethiscompanywhenthewarwasover,buttogivethemthe 84 opportunityofmakingthemostofGermanpatents. InadditiontoreplacingGermandrugs,alternativesweresought.Alcoholcouldreplace someoftherolesofphenol,buttheGovernmentcontinuedtoplacestrongrestrictionson
85 theuseofalcohol,asitwasalsorequiredforthemanufactureofexplosives. Companies
continuedtocomplainabouttheshortagesofalcohol,asitwasessentialasasolventfor
86 crystallisingdrugsandforpreparingChloral. Highgradecastoroil,glycerine,sugarand
87 lanolinwererequisitionedandfirmshadtokeepaccuraterecordsofuse. EvenaRoyal
TradeMarksofAlienEnemiesChemist&Druggist (19September1914):52F. H.Carr,TheWarandBritishProductionofFineChemicals,SyntheticOrganicDrugsand AlkaloidsTheBritishandColonialPharmacist(1915):4367,cuttingsin2131B/Carrat ImperialCollegeTradeMarksofAlienEnemiesChemist&Druggist(26September 1914):66SyntheticMedicalChemicalsBritishMedicalJournal (23January1915):168 AdvertBritishMadeHexamineTabloidChemist&Druggist85(17October1914):31 ConfiscatedDrugs,UseofTradeNames(14May1915),WF:85/31:12. 84 W.H.PerkininW.M.Gardner,(1915):422. 85 W.M.Gardner,(1915):322S.Miall,(1931):8486. 86 DutyFreeAlcoholintheChemicalIndustriesandCommercialUsesofAlcohol PharmaceuticalJournal 93(29August1914):31617,AlcoholandtheWarwith GermanyPharmaceuticalJournal 93(29August1914):33928,994proofgallonshad beenimportedfromGermanyin1913.AbsoluteAlcoholChemist&Druggist85.2(19 September1914):48.M.Fox,(1987):43. 87 F.H.Carr,FineChemicals,theirManufactureinRelationtotheBritishChemical Industry,presentationtotheSocietyoftheChemicalIndustry,Chemist&Druggist88.4
153
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
154
Commissiononsugarsupplywasestablished,andthishadaneffectondrugsassugarwas
88 neededtoproducepillcoatings. AccordingtoThomasE.LescherofEvans,Lescher&
Webb,whowashonorarysecretaryoftheWholesaleDrugTradeAssociation,greatstress waslaidonlargescaleproductionofsaccharinsothatpeoplecouldstilldrinktheirtea
89 andcoffee.
wouldbeheldfirmuntiltheendoftheyear.Therehadbeensomepanicbuyingandsharp
91 increasesin thepricesofdrugsandsurgicaldressingsandsomespeculativebuying. Two
pharmaceuticalmanufacturersservedonthepricescommittee,whichtriedtofixrealistic
92 pricesaccordingtosupplyanddemand.
Runcimanexpressedsympathyforthepleafrom thepharmaceuticalfirmsfor
93 protection,thoughasaLiberalheremainedafreetrader. Inordertoencourage
production,theGovernmentofferedaccesstorestrictedbuildingsupplies,promisedto defraycostsandassuredaguaranteedmarketduringthewarwithsignificantenhanced
(29July1916):778MajorGeneralSirW.G.MacPherson,(1921):1789:Burroughs WellcomeStandingOrders,WF:85/31:12W.J.Reader,(1970):285287. 88 SugarFurtherGovernmentActionChemist&Druggist85.1(31October1914): 33:LaterGlycerine,usedforflavouringdrugsandexplosiveswasbannedfromusefrom February1917bytheMinistryofMunitions(untilJanuary1919)soithadtobereplacedin pillsbyglucoseortreacle.W.J.Reader,(1970):2501. 89 T.E.Lescher,BritishPharmaceuticalCongress:PharmacyToday its ResponsibilitiesChemist&Druggist127.1(31July 1937):1189. 90 TheManufactureofPhenacetinChemist&Druggist85.2(12September1914): 38TradeMarksTheWarandtheShortageofDrugsChemist&Druggist85.2(19 September1914):512. 91 AProclamationRelatingtoTradingWiththeEnemyChemist&Druggist85.1(15 August1914):34TheWarandtheDrugTradePharmaceuticalJournal 93(8August 1914):219BuySpeculativePharmaceuticalJournal 93(15August1914):255Prices ofDrugsandMedicinesPharmaceuticalJournal 93(15August1914):2467,291War PricesChemist&Druggist85.1(1August1914):48. 92 ExportationofMedicinesChemist&Druggist85.2(19September1914):33. 93 L.F.Haber,(1971):188191.
154
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
155
94 salestothearmedforces. Furtherlongertermpromiseswerelessforthcoming.Early
BritisheffortsatreplacingGermandrugsweredescribedbyRuncimantotheGovernment
rd on23 Novemberaspartofacombinednationaleffortonascalewhichrequiresand
95 justifiesanexceptionalmeasureofstateencouragement.
salicylicacidtheystated: thatisaveryseriousconsideration,notonlyasregardssalicylicacidbut manyotherproducts,whichwecouldundoubtedlymanufactureprofitably, justaswehavebeenmanufacturingsyntheticperfumesformany 98 years. Towhatextentisafirmjustifiedinspendingcapitalonplantinthe presentcircumstances?Moneyisscarce.Noonehascouragetomakean expensivedrugonasmallscale.18monthsprewarweputdownnewplant formanufacturingat40,000p.a.Fewarethepeopleinthiscountrywho 99 arewillingtobeinterestedinfinechemicalsasactualmanufacturers. Thegovernmentagreedthattheexpensesofplantdevelopmentandadvertisingcouldbe offsetagainstroyalties,buttherewasstillreticencetoputdownplanttopreparecomplex drugsespeciallyif,asexpected,theabrogatedGermanpatentsmightnotremainworkable postwar. CharlesA.HillofBritishDrugHousessummarisedthecomplexityoftheissues facedbyBritishfirmsinpreparingsyntheticdrugswhenhewrote: Asregardssyntheticremedies,onecannotexpecttobuildupinafew months,anindustry,whichbystressofcircumstances,hasgrownupin Germanyduringtwogenerations.Thegreatdifficultyisthateachproduct hangsonothers,therawmaterialsforonesyntheticsubstancebeingtheby productinthemanufactureofanother.Notonlydoesthisdovetailingapply
94
TheManufactureofPhenacetinChemist&Druggist85.2(12September1914):
38.
95
96
155
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
156
totheproductsthemselvesbuttheapparatusandplantemployedare commontomanyproducts.Itwouldobviouslynotpaytoputdown expensiveplantforthemanufactureofafewproducts,thewhole consumptionofwhichisonlyamatterperhapshundredweights,butitwould easilypayafactorywhichwouldturnoutahundredproductseachwitha 100 consumptionofsomehundredweights. Maintainingsuppliesofessentialdrugsandchemicalswastoovitaltobelefttothe uncoordinatedactionsofindividualpharmaceuticalfirms,sothecontrolofsupplieswas coordinatedunderMoulton,initiallywithintheMinistryofSupply,thenundertheMinistry
101 ofMunitions,createdbytheMunitionsofWarActof9June1915. Oneofthechief
includingtheCabinetmemberandfreetradesupporter,SirAlfredMond,asthefirst
104 CommissionerofWorksin1916.
4.5BritishProductionofSalvarsanMRCTestingofQuality.
100
C.A.Hill,SyntheticMedicalChemicalsBritishMedicalJournal (23January 1915):168. 101 W.J.Reader,(1970):25051,258,26870A.J.P.Taylor,(1988):3031,34. 102 MondwasLiberalMPforSwansea,andamemberoftheABCMlaterW.J. Reader,(1970)I:272,447E.Hutchison,Minerva8(1970):392411. 103 M.R.Fox,(1987):4953. 104 A.J.P.Taylor,(1988):249KeithMiddlemassandJohnBarnes,(1969):8990.
156
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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Salvarsanwasthebesttherapyforsyphilis,whichwasdescribedastheworst
105 scourgeofwarasvenerealdiseaseaffectedoneinevery5ofthetroops. Inthecaseof
Thefirmstookadvantageofthe1909rulingthatonlythelatterstagesofproduction neededtobeperformedinBritain,usinglatestageintermediatesimportedfrom
108 Germany. Meister,Lucius&BrningwarnedattheendofAugust,whenthepatent
cameunderthreatthat: (Salvarsan)isextremelydifficulttoprepare.Ithastobepreparedbyvery scientificmen,insilvercrucibles.Eachdosehastobeverycarefullysterilised andverycarefullyweighedandispassedbythefirmMeister,Lucius& 109 Brningwhogiveaguaranteewitheverydosetheysendout. Mr.E.H.Scholl,theBritishbornmanagerofthepharmaceuticaldepartmentofMeister, Lucius,BrningatEllesmerePort,hadbeenbasedattheworksinGermanybeforemoving totheLondonofficein1907.HeofferedtomakealloftheSalvarsanrequiredbyBritain andgaveinformationonstockstoRobertMorantattheNationalHealthInsurance Commission.MembersoftheCommitteeonthesupplyoflaboratoryreagents,including
105
A.J.P.Taylor,(1988):121. ManufactureofSalvarsanProductsinEnglandandFranceBritishMedicalJournal (10April1915):649650W.H.Willcox,J.Webster,TheToxicologyofSalvarsan BritishMedicalJournal (1April1916):473,492493ReportoftheRoyalCommission ofVenerealDiseaseBritishMedicalJournal (30September1916):477. 107 W.J.Reader,(1970):2656 ChemicalTradeJournal 57(1916)no.1534: 329 1535:3523,358 ChemicalTradeJournal 61(1917),1589.367:ChemicalTradeJournal 65(1919)no.1676:1351. 108 M.R.Fox,(1987):50,52. 109 Chemist&Druggist(29August1914):41.
106
157
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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stafffromtheNationalHealthInsuranceCommission,weresenttoEllesmerePortto
110 evaluateproductionmethods. Theyreportedbackthatthesynthesiswouldnotbeeasy.
GermanpatentsforSalvarsanweresovagueastobeunhelpfulwithregardto
111 methodsofsynthesis. Furthermore,theGermanworkers,anticipatingwar,departedin
ThePresidentoftheAmericanbaseoftheFarbwerkeHoechstemphasisedthathe considereditimpossibleforeitherAmericaorBritaintosynthesiseSalvarsan: Idonotthinkthereisanypossibilityofengaginginthemanufactureof theseproductshere,eveniftherewerepatentlawstocompelthecarrying outofpatentsinthiscountryandmanufacturegoodsprotectedundersuch patents.EnglandhastriedthiswiththeresultthattheGermansestablished plantsinEngland,wherethey carriedoutjustenoughoftheprocesstocover thepatent,dependinguponGermanyforallrawmaterialsandintermediate products.TheresultisthatinspiteofitslawsEnglandislefthighanddry. OnlytodayIreceivedacablefromtheManchesterbranchoftheGerman plant,askingifwecouldsendanySalvarsantoEuropefortheBritish 113 army. HehadnoideathatBurroughsWellcomehadalreadyachievedthesynthesisofSalvarsan. Theoutbreakofthewaron4August1914changedtheimmediateresearchplansof BurroughsWellcome.Theydivertedresourcestoemergencyproductionofextratyphoid vaccines,tetanusanddiphtheriaantitoxinsandantigasgangreneseraunderAlexander
114 Glenny.Therewasanimmediateshortageoftetanusantitoxin. BurroughsWellcome
alsopreparedandstandardisedbiologicalpreparationsofdigitalis,ergot,squillsand
115 strophanthin.
110 111
NewPatentRulesChemist&Druggist85.1(29August1914):41. TheSalvarsanPatentsChemist&Druggist85.2(19September1914):51. 112 M.R.Fox,(1987):42,4952,55. 113 AmericanDruggistBritishMedicalJournal (26August1914):85.Thequote statesManchesterbutmustrefertoEllesmerePort. 114 H.J.Parish,WF:85/20:2:12. 115 Chemist&Druggist84.3(23May1914)EvansadvertSxiiEvansadvert PhysiologicalStandardisationChemist&Druggist85.1(15August1914)suppliii.
158
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
159
TheyalsorecognisedthatthesinglemostimportantsyntheticdrugdeniedtoBritain
116 wasSalvarsan,onwhichworkcommencedimmediately. HenryWellcomeappliedfor
hadappliedfortheSalvarsanpatents,complainingofunauthoriseduseandthatitwouldbe adangertothepublic.Theyrequestedroyalties,insistingthatitwasnotsoldunderits
118 tradenameofSalvarsanorreferredtoas606. Moreover,theywereveryeagerto
knowhowtheEnglishfirmwillsurmountthegreatdifficultiesinthepreparationand whetherthepatientswillhavetopayforthebusinessthoroughnesswithgrievousbodily
119 harm. TheyknewthatBurroughsWellcomehadbegunincorporatingGermanlinesas
andRemfryhadpreparedfurtheraromaticarsinicandarsonicacidsduring1908andmany
121 otherworkerswereinvolvedinsmallscalesyntheticprojects.
116
A.Duckworth,RiseofthePharmaceuticalIndustryChemist&Druggist172 Centenarynumber(10November1959):127139Diphtheriaantitoxinincreasedfrom240 mUnitsin1910to480mUin1915and640mUin1920,WF:84//7:1213. 117 TheSalvarsanPatentsChemist&Druggist85.2(19September1914):51. 118 ibid. 119 Quotedfrom Chemist&Druggist85.2(14November1914):49. 120 MrHogg,HistoryoftheWorksvol.III,WF:S/G/145. 121 H.King,FrankLeePymanBiographicalMemoirsofFellowsoftheRoyalSociety 4(1944):684.
159
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
160
specificallyexcludedprotectionofmedicinesandasaresultworkersatthePasteur
124 Institutehadalreadypreparedthesyntheticarsenical,Atoxylin1907. Thisexperience
helpedPoulenctoproduceSalvarsan. AresearchteamwasestablishedatBurroughsWellcomespecificallytomanufacture
125 Salvarsancommercially. Thefirstfullbatchof46gramswasproducedon23October
126 1914,thoughitwaspoorlysoluble. By7November1914acontinuousproduction
sampleforfurthertestsand6vialsweresenttoadoctorforac.(clinical)trial.Overthe
122
GermanPatentsandTradeMarksPharmaceuticalJournal 93(24October1914):
601.
123
May&BakercollaboratedwithPoulencprewarconcerningthepricingofiodides, bismuth,mercurialsandquinine,GermanPatentsandTradeMarksSalvarsan PharmaceuticalJournal 93(14November1914):675.May&BakeralsosoldEpsomsalts, bathsalts,sodiumsulphateandseveralGermanimports.BritishMedicalJournal (13 August1914)SupplF.H.Carr,FineChemicals:TheirManufactureinRelationtothe BritishChemicalIndustryChemist&Druggist88.4(29July1916):7789C.A.Hill,T. D.Morson,TheBritishAssociation TheSyntheticChemicalIndustryChemist& Druggist88.4(9September1916):9512. 124 WalterSneader,DrugDiscovery:theEvolutionofModernMedicines (London: JohnWiley,1985):2523. 125 TheseincludedFrankPyman,RobertFargher,HubertWilliamBentleyClewer, EdwardJones,AlfredBacharach,HaroldKing,RobertReginaldBaxter,EdwardCharles SnellJones,WF:Box25.PymanandClewerworkedonneosalvarsanfromNovember 1914.WF:YLBox46WorksRecords. 126 G.E.Pearson,AChronologyoftheHistoryofBurroughsWellcome&Co.1878 1936(typescript),WF:88/24:41d:12. 127 TheToxicologyofSalvarsan:Dioxydiamidoarsenobenzol(Salvarsanor Kharsivan)British MedicalJournal (1April1916):4738.
160
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
161
nextyearandahalf,over130furtherbatchesweresenttoDrLeesintheanalytical
128 department.
outstandingserviceasDirectoroftheWPRL.FrankPymanfromtheExperimental DepartmentwasgiventheaddedresponsibilitytotakeoverthepreparationofSalvarsan
130 andneosalvarsanfrom1December1914.
128
WF:90/31KharsivanQArecordbook(23October1914to17November1915), AccessionBox160. 129 StaffatWCRL,WF:Box25EvansChemist&Druggist88.4(29July1916): 775. 130 PersonalitiesFrederickB.PowerRetirementChemist&Druggist85.2(7 November1914):15WF:Box25Powermaintainedcontactwithhisformercolleagues, Dale,HenryandTutinaslateas1925e.g.DaletoPower,(25June1924).HenrytoPower, (27January1925)FrankTutin(UniversityofBristol)toPower(7July1925),WF:88/94: 49. 131 ConversationswithF.H.CarrbyA.E.Guenther,B.CARRFH6,ImperialCollege.
161
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
162
specificallynamedasinvolvedinSalvarsanproduction.TheseincludedRobertFargher D.Sc.andRobertR.Baxter,bothofwhomhadtrainedinManchesterunderW.H.
137 Perkin. HubertWilliamBentleyClewer(atBurroughsWellcome191418)andEdward
C.S.Jones(191318)wereinvolvedinneosalvarsananalysesbetweenNovember1914and
138 January1915.
WorksHistory,StaffRecords,WF:YL46. WF:RecordsofKharsivan thiswasuncataloguedatthetimeofmyresearch. Recordofbatches1132. 134 WorksHistory,StaffRecords,WF:YL46. 135 ThisalsoproducedsalicylicacidfromJanuary1915,sodiumsalicylatefromMarch 1916,phenacetinfromMayandAspirinfromSeptember1916:G.E.Pearson,(1936), typescript,WF:88/24:41d:12. 136 TheLaboratorybooksof41chemistsdetailtheextentofchemicalsyntheticwork undertaken:WF:85/9bundles58Accessionbox5. 137 StaffatWCRL,WF:Box25. 138 HubertCleweralsoworkedondigitalis,chaulmoograoil,emetineandpyramidone andJonesalsoproduceddigitalisandsalicylicacid.Fargherproducedalkaloids,pilosine derivatives,hydroquinone,benzylchloride,lysidineandsalol,WorksHistory,Staff Records,WF:YLBox46.
162
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
163
PublicHealthattheUniversityofAberdeenFrederickGowlandHopkins,founderof
139
W.S.Feldberg,HenryHallettDale18751968BiographicalMemoirsofFellows oftheRoyalSociety 16(1970):106. 140 BritishMadeSalvarsanPharmaceuticalJournal 94(17April1915):536. 141 Dr.ChristopherAddisonwasM.P.forHoxtonandProfessorofAnatomyat UniversityCollegeandSheffield.IntheWarhewasMinisterforReconstructionfrom1917 andPresidentoftheLocalGovernmentBoard.Hewentontoarrangethecharterforthe MRCandwasthefirstMinisterofHealth,establishingaCommitteewithLordAthloneon theprovisionofpostgraduatemedicaleducation.JoanAustokerandLindaBryder(eds.), (1989):24,222. 142 SirJohnLedingham,WilliamBullochObituaryNoticesofFellowsoftheRoyal Society 3(1941)81952.
163
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
164
withWellcomesreorganisationin1913,placingAndrewBalfourasDirectorofthe WellcomeScientificBureauwithoverallresponsibilityforallofthelaboratories.Dalefelt
146 thatasaresultthelaboratorieswouldbelessindependent.
NosoonerwastheMRCestablishedon1JulythanthewarbrokeoutinAugust
147 withwhatatthetimeonlyseemedafewdaysnotice. BargerandDalereturnedrapidly
fromavisittoGermany,andsoonafterBargermovedtoEdinburgh.AlmrothWright
148 decidednottomovefromSt.MarystotheNIMR. OfhisstaffonlyLeonard 149 150 151 Colebrook movedtotheNIMR,underCaptainS.R.Douglas. W.E.Gye,
previouslyattheImperialCancerResearchFund,wasadded.
143
SirH.Dale,FrederickGowlandHopkinsObituaryNoticesofFellowsoftheRoyal Society 6(1948)115145. 144 L.BryderinJ.AustokerandL.Bryder(eds.),(1989):56. 145 BargerwasProfessorofChemistryatGoldsmithsCollege,NewCrossfrom1909 andatRoyalHollowayCollegefrom1913.HeservedtheCounciloftheChemicalSociety 19137.In1919hetooktheChairofChemistryinRelationtoMedicineatEdinburgh whereheremaineduntilayearbeforehisdeathwhenhebecameRegiusProfessorof ChemistryattheUniversityofGlasgow.SirH.H.Dale,G.Barger,Biographical MemoirsofFellowsoftheRoyalSociety (1940)3:6385. 146 LieutenantColonelAndrewBalfourhadbeenfirstDirectoroftheTropical laboratoriesinKhartoumfrom1902.DalequestionedPearsononhisplans:DaleArchives, RoyalSociety,HD143.6:67. 147 DaleArchives,RoyalSociety,HD47.13.144. 148 CommentsonalecturebySirC.Harrington,23November1963. DaleArchives,RoyalSociety,HD47.12.12. 149 C.L.Oakley,LeonardColebrookBiographicalMemoirsofFellowsoftheRoyal Society 17(1971)17:91138. 150 P.Laidlaw,StewartRankenDouglasBiographicalMemoirsofFellowsofthe RoyalSociety (1935)1:56976. 151 C.H.Andrewes,WilliamEwartGyeBiographicalMemoirsofFellowsoftheRoyal Society 8(1953):41930J.AustokerandL.BryderinJ.AustokerandL.Bryder(eds.), (1989):42.
164
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
165
ThemovementofBurroughsWellcomestafftotheMRCdecimatedthefirms capacitytoperformstandardisationwork,butleftthemwellplacedtocollaboratewiththe
152 MRC. Fortunately,thepreviousworkattheWellcomelaboratoriesattractedfurther
highcalibreresearchers. JoshuaHaroldBurnjoinedBurroughsWellcomefromCambridge
153 inJanuary1914 andcontinuedJowettandPymansresearchonnicotineand 154 pilocarpine. However,withtheoutbreakofwar,Burnalsolefttoregisterasamedical 155 student,andtoserveinFrance.
152
Afurtherresearcher,HaroldKingjoinedtheMRCfromBurroughsWellcomein 1919 SirCharlesHarrington,H.KingBiographicalMemoirsofFellowsoftheRoyal Society 1956)2:15771. 153 BurnstudiedphysiologyatEmanuelCollege,Cambridgein1909underF.Gowland HopkinsandjoinedtheWPRLon1January1914:E.Buelbring,J.M.Walker,J.H. BurnBiographicalMemoirsofFellowsoftheRoyalSociety (1981):4589. 154 J.H.Burn,H.H.Dale,TheActionofCertainQuaternaryAmmoniumBases, JournalofPharmacology 6(1915):305. 155 E.Blbring,J.M.Walker,J.H.Burn(1981):4589. 156 Laidlaw'spostattheNationalInstituteofMedicalResearchcamewithasalaryof 750perannum:MRCAnnualReports191420MRCCommitteeMinutesII,(16 December1921):167.
165
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
166
licensefromtheBoardofTrade,andthisrequestwasreferredtoasubcommittee includingFletcherMoulton,FrederickGowlandHopkins,andWilliamBullochasaresult
157 theSalvarsancommitteemetforthefirsttimeon29October1914. Theproposalfor
MRCinvolvementwasacceptedon10December1914withtheconditionthattheMRC nameappearedonanyvialstestedbythem.ThissuitedBurroughsWellcomeasitcouldbe
158 exploitedintheiradvertisements. PreWartherehadbeennoformalisedtestingof
EwinsconcentrateduponexaminingarsenicimpuritiesinsamplesofSalvarsanandother
160 organicarsenicals.
OccasionalbatchesweresubstandardandthisfurtherestablishedthecaseforMRC
162 controlofthequalityofthesophisticatedsyntheticandbiologicaldrugs. ByApril1915
theMRCwereabletostate:atanearlydatetheexperimentalworkwhichhasbeendone
157 158
MRCMinutesI,(29October1914):4. MRCMinutesI,(10December1914). 159 DaleArchives,93HD143.11:3. 160 A.J.Ewins,TheEstimationofArsenicinOrganicCompoundsJ.Chemical Society 109(1916):1355. 161 W.S.Feldberg,HenryHallettDaleBiographicalMemoirsofFellowsoftheRoyal Society 16(1970):1067. 162 DaleArchives93HD,NIMR47.13.144.
166
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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undertheirdirectionshowedthattheproblemofthesuccessfulmanufactureofSalvarsan
163 compoundsinEnglandandFrancehadbeensolved. TheMay&Bakerversionof 164 Salvarsanpassedeverytime,butoccasionallytheBurroughsWellcomeversionfailed.
TheMRCwerekeentogainabetterunderstandingoffactorsinfluencingthepotencyand safetyofthenewBritishsyntheticdrugsandwhenbatchesofBurroughsWellcomes
165 Kharsivanwerereleased,thedrugwastestedinalargenumberofpatients. Willcoxat
BritishsyntheticdrugswereasgoodastheGermanversions.Followingtheirexperience withSalvarsan,theMRCextendedtheirlaboratorytestingtoincludevariousseraand
167 antitoxins,whichhadpreviouslybeenimported. However,thequestionsthatcontinued
163 164
BritishMadeSalvarsanPharmaceuticalJournal 94(17April1915):536. DaleArchives,93HD143.11. 165 H.C.Lucey,TheTherapeuticandReactionEffectsofKharsivan.ARecordof600 InjectionsBritishMedicalJournal (29April1916):6146. 166 W.H.Willcox,J.Webster,ToxicologyofSalvarsanBritishMedicalJournal (1 April1916):4738. 167 MRCAnnualReport,191415,(London:HMSO,1916):4244.
167
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
168
availablechemistswithexperienceoflargescaledrugproduction.Chemistryinindustry didnotofferarewardingcareeraspaywasgenerallyinadequateandtheemployerlooked
169 toooftenonlyforimmediateprofit. Thus,itwasasignificantlossevenwhen
168 169
SyntheticMedicinalChemicalsBritishMedicalJournal (23January1915):168. W.Tilden,BritishMedicalJournal (23January1915):168. 170 Chemistry&Industry (23February1963):303. 171 S.Chapman,(1974):9698S.A.B.Kipping,TheResearchDepartmentofBoots PureDrugCo.Ltd. Chemistry&Industry (23February1961):30210W.H.Sims, Notes,8November1963Bootslibrary.CorrespondencefromBootslibrarian.
168
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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AtthestartofthewarBootshadbeenheavilyadvertisingwarrelatedlow technologyproductssuchasantiflyspray,verminpowdersandcompressedmedicinals
172 forthemenatthefront. CarrwasagoodfriendofE.F.Harrisonwhohadperformed
hadsecuredCarrisnotclear,buttherecordsatBurroughsWellcomeshowthatCarrdid
175 notdepartuntil10November1914. Attheendof1914Bootsextendedtheir
172 173
C.Weir,JesseBootofNottingham (Nottingham:Boots,1994):5559. F.H.Carr,HarrisonMemorialLecture,PharmaceuticalJournal 103(26July 1919):9399. 174 S.D.Chapman,(1974):96. 175 StaffRecords,WFS/G/145. 176 S.D.Chapman:(1974):96.
169
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
170
177 processesusedhehadpracticalexperienceinmanufacturingofalloftheirmainlines.
TheacquisitionofChapmanandPorter: Enablesacompetingfirminwhoseservicestheyaretoobtainalmost completeinformationastothefirmssecretprocessesandspecially knowledgeinthemanufactureofcompresseddrugs.Thecombinationof CarrwithChapmanenablesthemtoproducegranulesaccordingto BurroughsWellcome&Company formulaeandtheacquisitionofFidler enablesthemtousesimilarmachinesandpunchesandeyeswhilstthe additionofPorterenablesthemtoobtainteaofasimilarcharactertothat usedbyBurroughsWellcome&Companyandtocompressitonamachine,
177
H.A.D.JowettMemoonSecretProcesses,BAS/G/49,(13January1916),File 85ReportfromVariousSourcesre.'B'affairBootsHeadhuntingBurroughs WellcomeStaff,1915,WFBox10. 178 WorksRecords,WF:Box25. 179 Re.SecretProcesses,Mr.CarrmightdenythisknowledgebutH.E.Wilson couldnot,havingactuallymadethesolutions.WF:D3:DWBox15,BAS/G/49.Hehad chargeoftheformulaebooks,(12January1916).WFBox10WF:D3. 180 Re:FormulaeandSecretprocesses,WF:YLBox25,WorksRecords.
170
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
171
thedesignofwhichisentirelyduetoBurroughsWellcomeand 181 Company. TheinternalenquiryheldbyBurroughsconcludedthat: TheacquisitionofCarr,WilsonandThompsonbyafirmwould enablethemtoobtainandworkthemoreimportantsecretprocesses workedoutbyBurroughsWellcome&Co.Mr.Carr,havingthe generalknowledgeofalltheprocesses,Wilsonbeingacquaintedwith themanufactureofquininesaltsandglycerophosphates,chloroform andpossiblyorganics,whileThompsonwouldsupplythedetailed 182 practicalknowledgeforthemanufactureofalkaloids. BythistimeBurroughsWellcomehadproducedseveralalkaloidsandsynthetic
183 drugs. Thompsonhadproducedsolanaceousalkaloids,eserine,emetine,pilocarpine, 184 hydrastine,homatropine,cocaine,andergotoxine. Bootswouldnowbeabletomakeall
departmentatthetime,Mr.H.B.Holthouse,recruitedfurtherchemistsin1916,including
186 Belgianrefugees. HealsorecruitedW.H.Simswhogaveavividaccountofhisearly
timeatthecompany.SimsworkedinitiallyasanassistanttoThompson,preparing
187 alkaloidsandglucosidesofDigitalis.
IttooktimeforBootstoestablishtheirnewmanufacturingcapacitybutthey producedtheantisepticChloramineTin1916andexpandedtheirfactoryfurtherduring
181 182
ReportsfromVariousSourcesre.'B'Affair1915,WF:Box10. ReportsfromVariousSourcesre.'B'Affair1915,WF:Box10. 183 Fargherproducedalkaloids,pilosinederivatives,hydroquinone,benzylchloride, lysidineandsalol.EdwardJonesproduceddigitalisandsalicylicacid.HubertWilliam BentleyClewer,(191418)workedondigitalis,chaulmoogra,emetineandpyramidone. PymanandClewerworkedonneosalvarsanfromNovember1914,WF:YLBox25,Works Records. 184 F.L.Pyman,WarWorkattheWCRL,WF:Box25DW. 185 C.Weir,(1994):56. 186 SimsworkedwithC.A.Hudson,F.R.Parkin,andF.A.H.Stowellprepared hyoscineandhomatropine.W.H.Sims,Notes,8November1963,Correspondencefrom J.M.Leverton,LibrarianatBootsDrugCompanyS.D.Chapman,(1974):96C.C. Weir,(1994):59. 187 W.H.Sims,Notes,(8November1963).
171
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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departmenttoextractatropinethewartimeproductionreached400ouncesperweek.In ordertomeetthesedemandsitwascommonforstafftowork12hourseachdayandat
189 weekends. InpreparingsyntheticAdalin(diethylbromoacetylurea)andFlavineas
safewoundantiseptics,CarrcollaboratedwithProf.F.S.KippingatUniversityCollege,
190 Nottingham,whosesonwasachemistatBoots. Carrinitiallytriedtomakethe
AsBootswereencouragedbyearlywartimesuccess,Carrattractedfurther BurroughsWellcomestaffincludinganexpertintabletmanufacture,anauthorityon
188
TheReportoftheRoyalCommissiononVenerealDiseasesBritishMedicalJournal (11March1916):3867. 189 W.H.Sims,Notes,(8November1963):2:Bootslibrary. 190 S.A.B.Kipping,TheResearchDepartmentofBootsPureDrugCo.Ltd. Chemistry&Industry (23February1961):30210C.H.Browning,R.Gulbransen,E.L. Kennaway,L.H.D.Thornton,FlavineandBrilliantGreen,PowerfulAntisepticswith LowToxicityfortheTissuestheirUseintheTreatmentofInfectedWoundsBritish MedicalJournal (20January1917):7378. 191 F.H.Carr,BritishChemicalIndustryChemist&Druggist 88.4(29July1916): 799800. 192 TheManufactureofAdalinChemist&Druggist89.1(27January1917):106. 193 H.D.Dakin,J.B.Cohen,J.Kenyon,StudiesinAntisepticsII:onChloramineits Preparation,PropertiesandUseBritishMedicalJournal (29January1916):1602:H.D. Dakin,E.K.Dunham,AHandbookonAntiseptics(NewYork:MacMillan,1918):46
172
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
173
pharmaceuticsandfivemorechemistsfromLeedsUniversityincludingA.NutterSmith (tablets),B.A.Bull(pharmaceuticals)andDr.MarshallwhohadtrainedunderProfessor
194 ArthurG.Green. AttheendofthewarFrancisCarrwasawardedtheC.B.E.forhis 195 teamswartimecontributions.
DartfordunderPymanon30September1915andproducedsalicylicacid,andAspirinby
TheReportoftheRoyalCommissiononVenerealDiseasesBritishMedicalJournal (11 March1916):3867. 194 S.Chapman,(1974):9697. 195 CarrreceivedtheC.B.E.whileotheruniversitychemistswereawardedanM.B.E. orO.B.E.C.Weir,(1994):59. 196 F.A.Pickworth,born31August1889,B.Sc1913,qualifiedanalyst1914,died22 October1967,WF:86/68Obituary,F.A.PickworthBritishMedicalJournal (11 November1967):363Obituary,F.A.PickworthBritishMedicalJournal (2December 1967):559Obituary,F.A.PickworthBritishMedicalJournal (10February1968):387. ThequoteisfromChemists,F.A.Pickworth191117,WF:86/68
197
H.H.Dale,G.Barger,(1940)3:6385.
173
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
174
thatIamagainwithoutanypharmacologicalassistantanditisimpossibletodoanytests
200 forseveralweeks.
ofapharmacist,CharlesGillingwhospenttimeinFrancelearningtheprocedures.As agreedwithBurroughsWellcome,batchesthatpassedwerealsogivenlabelsbearingby
203 authorityoftheMRC.
198
C.R.Harington,H.King(1956):158.KingstayedatBurroughsWellcomeuntil hismovetoSouthAfricain1947. 199 G.E.Pearson,(1936),typescriptWF:88/24:41d:12. 200 O'BrientoTaylor,StandingOrders,(1February1917),WF:85/31:12. 201 H.H.Dale,ArthurJamesEwins(1958):88. 202 Judy Slinn,(1984):923HenryDale,ArthurJamesEwins(1958):8191.
174
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4.8ProductionofFurtherSyntheticDrugsandAlkaloidsinBritain.
Byearly1915manyBritishfirmsproducedawiderangeofnewalkaloidsand
205 206 chemicals. A.BoakeRobertsproducedtheoils,cineol,menthol,andoenanthicether.
In March1915,W.J.BushofHackneyandThomasKerfootinManchesterwerethefirst
208 inBritaintoproducesalicylatesusedforrheumatism,influenzaandneuralgia. At
203
204
MRCMinuteBookI,(10&13December1914). WF:YLBox25. 205 Howard'sJ.F.McFarlan,Morson's,T.H.Smith,DuncanFlockhardtandMay& Bakerproducedemetine,digitalisandcocaine,andnewalkaloidsofipecacuanha.In1915 theyproducedsynthetichistidine,lysidine,cresols,localanaesthetics,glycerophosphates andpilocarpine:SocietyoftheChemicalIndustryChemist&Druggist86.2(6March 1915):53W.J.Reader,(1970):258,2678M.R.Fox,(1987):4849,8688Evans PhysiologicalStandardisationChemist& Druggist85.1(15August1914),Suppliii. 206 SocietyoftheChemicalIndustryChemist&Druggist86.2(6March1915):53. 207 Evansadvertin Chemist&Druggist85.2(29August1914):33WhatisaFine Chemical?Chemist&Druggist85.2(29August1914):51G.Tweedale,AttheSignof thePlough:275YearsofAllen&Hanbury'sandtheBritishPharmaceuticalIndustry1715 1990 (London:Murray,1990):78,85DuncanFlockhardtadvertsChemist&Druggist 88.4(29July1916):147. 208 ManufactureofSalicylicacidChemist&Druggist85.1(22August1914):3738 A.H.Cox,ThePatrioticPosterChemist&Druggist85.2(5September1914):1.
175
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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Howards,eventhoughonlytheseniorpartnerswerechemists,theymadeAspirinbya
209 batchprocesseasytoproduceonalargescale, intheirsplendidrangeofuptodate
210 laboratories. Howardsmadeasmuchquinineastheycouldwithavailablesuppliesof 211 bark.
heavilyinmanufacturingfacilitiesaroundGrahamStreetinLondon.Afurther3acreswere boughtontheoppositesideoftheRegentsCanal.Inadditiontoshortagesoffundsand buildingmaterialstherewerealsostaffshortages.BDHhad150enlistedmenandthese werereplacedby150womenandbyasmanyoldermen.AnewUStelephonesystemwas installedandanextendedautomatedpilldepartmentwith facilitiesforfinishingandcoating. Hillwrote:OurpolicyinregardtotheproductionofsocalledGermanchemicalshasbeen tomanufacturethosearticleswhichwouldotherwisebeunobtainable.Hexaminewas madeatthestartofthewarbutwasdiscontinuedwhenthereweresufficientsupplies. Manytonsofsalicylicacidandsodiumsalicylateswereproducedbutthelimitingfactorhad
214 beenplantcapacityasincreasedmanufactureisdoneattheexpenseofsomethingelse.
ArthurH.CoxadvertisedinhisPatrioticPosterthat:Wecannottakeuparmsagainst ourcountrysenemybutwecan....putupagrandfightforourcountrybyrefusingtobuy
215 Germangoods. BritishwholesalerswhohadpreviouslydistributedGermandrugssuch
209
QuotedfromAfterOneYearofWarTheSupplyofFineChemicalsChemist& Druggist87.1(14August1915):45foraphotographofHowardsofIlfordfactorysee Chemist&Druggist88.4(29July1916):127. 210 HowardsofIlfordChemist&Druggist85.1(1August1914):suppl.iiiii. 211 H.S.Abrahamson,TheWarContract,Chemist&Druggist99.2(3November 1923):62526. 212 WhatisaFineChemical? Chemist&Druggist85.1(29August1914):51. 213 TheBDHGuidetotheBritishPharmacopoeia1914 (London:BritishDrugHouses, 1915)atWellcomelibrary. 214 AQuinquennialRecord.HowtheBDHhavegrownsincethe4ConstituentHouses MergedintoOne,Chemist&Druggist88.4(29July1916):78889. 215 Quotedfrom BritishMedicalJournal (12September1914):43C.Fearon,The HistoryofA.H.Cox&Co.Ltd.PharmaceuticalHistorian 23(1993):46Aphotograph
176
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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asLysol,forScheringnowemphasiseditwasmadebyaBritishfirmwithBritishcapital,
216 byBritishlabour,usingBritishrawmaterials. EvansSons,Lescher&Webbgrew
Within3weeksofthestartoftheWar,ImperialCollegeofSciencemade23synthetic
219 drugsonasmallscale. DuncanFlockhardtdistributedmedicalanddieteticpreparations,
vaccinesandtuberculinmadebystaffattheRoyalCollegeofPhysicians,Edinburghunder
220 221 Prof.Ritchie, andtheListerInstituteproducedadditionalvaccines.
collaboratedwithEvansSons,Lescher&Webbthroughanadvisoryboardestablishedin
223 July1917. ThelaboratoriesatLiverpool,likethatatOxfordwereoccupiedby
colonistsfromindustrytakingadvantageofuniversityfacilitiesforproduction.Oxford
224 hadrepresentativesofBritishDyes,W.J.BushandBoakeRoberts. HenryDakin
oftheA.H.Coxlaboratoriesisshowninanadvertin Chemist&Druggist88.4(29July 1916). 216 LysolChemist&Druggist86.2(6March1915):8. 217 ACheeryChatwithSirEdwardEvansontheWarsEffectonBritishPharmacy Chemist&Druggist88.4(29July1916):7756. 218 TrevorI.Williams,(1990):91. 219 TheImperialCollegeofScienceBritishMedicalJournal (3June1916):800The WarandtheSupplyofDrugsBritishMedical Journal (10March1917):339. 220 MedicinalandDieteticPreparationsVaccinesandTuberculinsDuncan FlockhardtBritishMedicalJournal (17March1917):367. 221 TheListerInstituteBritishMedicalJournal (20May1916):728. 222 LordToddandJ.W.Carnwath,RobertRobinson18861975Biographical MemoirsofFellowsoftheRoyalSociety 22(1976)415527. 223 LordTodd,J.W.Carnforth,RobertRobinson(1976)GeoffreyTweedale, (1990):120. 224 TrevorIWilliams,(1990):91.
177
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producedflavinestomakeChloramineTinassociationwithProf.J.B.CohenatLeeds,as partofhisworktodevelopantisepticsthatdidnotbreakdownoncontactwithwounds,as
225 hypochloritesdidandBrowningandothersinvestigatedthese. W.E.S.Turneratthe 226 UniversityofSheffieldofferedtosupplyauthoritativeinformationonpatents. Etherwas 227 alsopreparedatGovernmentfactoriesinquantitiesupto5,000tons.
availableinBritainfromAmericanfirmssuchasAbbott,whileSmith,Kline&Frenchsold
229 antiseptics. Thewartransformedtheproductionofalkaloids,syntheticchemicals,and
4.9.1EstablishmentoftheAssociationofBritishChemicalManufacturers(ABCM).
225
MedicalResearchCommitteeTheAntisepticFlavine(Acriflavine)British MedicalJournal (9June1917):76970E.K.Dunham,H.D.Dakin,ReporttotheMRC, ObservationsonChloraminesasNasalAntisepticsBritishMedicalJournal (30June 1917):8657DakinsDiChloramineTintheTreatmentoftheWoundsofWarBritish MedicalJournal (25August1917):24951.ChloraminewassoldbyBurroughsWellcome asHalozane,H.D.Dakin,E.K.Dunham,TheDisinfectionofDrinkingWaterBritish MedicalJournal (26May1917):682HealthofMunitionsWorkersBritishMedical Journal (7July1917):13C.H.Browning,R.Gulbransen,L.H.D.Thornton,The AntisepticPropertiesofAcriflavin,ProflavineandBrilliantGreen,withSpecialReference totheirSuitabilityforWoundTreatmentMRCReport,BritishMedicalJournal (21July 1917):7075C.H.Browning,R.Gulbransen,E.L.Kennaway,L.H.D.Thornton, FlavineandBrilliantGreen.PowerfulAntisepticswithLowToxicitytotheTissues:their UseinInfectedWoundsBritishMedicalJournal (20January 1917)I:7378. 226 Chemist&Druggist85.2(12September1914):40. 227 ThePharmaceuticalJournalandPharmacist(14February1910)inB.CARR 228 W.J.Reader,(1970)I.:266,276. 229 L.F.Haber,(1971):144.TheAmericans,inthesamesituationpassedasimilarlaw in1917.
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UnlikeGermanyin1914,Britainhadnotradeassociationrepresenting
230 pharmaceuticalmanufacturingfirmstocoordinatewithcentralgovernment. Inpartthis
functionhadbeentakenupbythemoreacademicallyoriented,SocietyoftheChemical Industry.Attheirannualconferenceon7November1914theSocietydiscussedthe
231 PresentandFutureoftheBritishChemicalIndustryasAffectedbytheWar.
Sincetheoutbreakofwar,severaloftheseniorstaffofBritishfirmswereforcedto collaboratecloselyonthevariousgovernmentcommitteesinordertoevaluatewhichdrugs theycouldmakeandwhichchemicalintermediateswereneeded.Insharingtheproblems andchallengesthesekeyindividualsrecognisedthepotentialadvantagesofestablishing moreformallongertermcollaborationsin whichtheindustryhadacollectivevoice. Previouslymanyfirmsproducedthesamelinesandeachcoordinatedtheirownsuppliesof rawmaterials.Theyreliedindividuallyondyefirms,includingthoseinGermanyfor chemicalintermediatesandalsoreliedontheBritishdyestuffsconsultantsasacampaigning voice. MembersoftheChemicalSociety,theSocietyofDyeists&Colouristsandthe SocietyfortheChemicalIndustryestablishedaJointCommitteetoorganisethechemical manufacturerstoaddresstheissuesnotcoveredbyothercommitteessuchaswhichless commonchemicalintermediateswereneeded,investmentinmanufacturingplant, coordinationofproductionandthelackoftrainedchemists.Thefirstjointmeetingforall memberswasheldon27May1916intheroomsoftheChemicalSociety,underthe
232 chairmanshipofthePresidentoftheChemicalSociety,AlexanderScott whoexplained:
230
231
L.F.Haber,(1971):232. TheProductionofFineChemicalsinBritainPharmaceuticalJournal 93(14 November1914):696. 232 ScottwasalsoamemberoftheSocietyoftheChemicalIndustry:T.S.Moore,J.C. Phillip,TheChemicalSociety18411941.AHistoricalReview(London:TheChemical Society,1947). 233 ThequoteisfromABCMChemist&Druggist88.3(27May1916):3941, FurtherbackgroundontheABCMisgivenonpage87.
179
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The16membersoftheorganisingcommitteeoftheABCMincludedoneFellowofthe
234 RoyalSociety,twoDScsandfiveFellowsofRoyalInstituteoftheChemicalSociety.
ThefirstDirectoroftheABCMwasW.J.UglowWoolcock,formercommitteememberof theSocietyoftheChemicalIndustryandofthePharmaceuticalSociety.Boakesuggested
236 thattheABCMshouldbelimitedtoBritishfirms.
234
OrganisingChemicalIndustryChemist&Druggist88.3(27May1916):3941.At themeetingon22June1916thefollowingwerecooptedSirA.Mond,Mr.F.W.Brock, Mr.G.B.Merrian,Mr.MaxMusprattF.R.S.ofLiverpool,Mr.R.B.Pullar,MrA.T. Smith,MrNormanHolden,MrJohnGray,MrW.J.Wilson. 235 E.F.ArmstronghadstudiedattheRoyalCollegeofScienceinLondon,thenthe CentralTechnicalInstitute,gaininghisPhDatBerlinUniversityandD.Sc.fromLondon University.HehadbeenaDirectoroftheSouthMetropolitanGasCo.,thenscientific advisortotheMinistryofWorksandMinistryofHomeSecurity.Hehadmanagedother firmsbeforebeingappointedManagingDirectoroftheBritishDyestuffsCorporationin 1925,C.S.Gibson,T.B.Hilditch,EdwardFranklandArmstrongObituaryNoticesof FellowsoftheRoyalSociety 5(1948)619633. 236 Chemist&Druggist88.3(27May1916):39,41,87. 237 Chemist&Druggist88.3(24June1916):665ABCMChemist&Druggist88.3 (1July1916):35ABCMChemist&Druggist88.4(22July1916):36British ChemicalIndustry:OneYearOnChemist&Druggist88.4(29July1916):45Afterthe WarHowStandOurChemicalIndustries(ChemicalSectionoftheLondonChamberof Commerce)Chemist&Druggist88.4(4November1916):1110SecretsofChemical Manufacturers,ABCMChemist&Druggist88.4(11November1916):1134Salvarsan SeveralFatalities,AlcoholPrices(18November1916):1148,SecretChemical ProcessesChemist&Druggist(18November1916):1160.
180
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andlackofchemicalknowledgebyGovernmentofficials,andpointedoutthattheImperial
239 CollegeofSciencehadmanybuildingsunequippedthroughwantoffunding. The
ABCMbelievedthattheseproblemscouldbeovercomeiftheABCMfinancedand supervisedresearchincooperationwithteachinginstitutions,intheinterestsofthe chemicalindustryasawhole,andmakingthisavailabletomembers.Itwouldorganise systematicconferencesbetweenmanufacturersandteachers.Regardingwartimesupplies, theABCMhadtoensurethateventheunusualbutimportantchemicalswerefreely available.Theyappointedachemicallytrainedadministratortoworkwithagoverningbody ofacademicprofessionalstokeeprecordsofallBritishchemicalproductsandtheir manufacturers,avoidingduplicationandunnecessarydevelopmentofplant. Pharmaceuticalmanufacturerswarnedthat:TherealestablishmentofaBritishfine chemicalindustryuponanadequatescalecannottakeplaceuntilthenaturalresourcesin
240 materials,plant,labourandchemicalknowledgearefreelyavailable.
OneoftheleadingABCMmen,FrancisCarrgaveapapertotheSocietyofthe ChemicalIndustryon20July1916inwhichherecalledhowcapitalistsandbankerswere reluctanttoinvestinthepharmaceuticalindustry.TheGermanstrategywastochargehigh pricesforintermediates,arrangelongtermcontractsandsystematicdumpingofdrugs. Hecontinued: Representativesofeachbranchofthechemicalindustrymustdefine theextentoftheirrequirementsfromotherbranches.Welooktothe ABCMtotaketheleadinthesemattersandtosetafootthenecessary organisationtopreventoverlappingandgaps,toarrangebymutual concessionsthattoomanydonotmanufacturethesamechemicals, andtosecurethemanufactureofthosechemicalsalreadyprovided for.AfurtherfunctionoftheAssociationwastocalluponcertain branchesofchemicalmanufacturertosupplyrawmaterialssuchas
238
JohnTomlinsonBrunnerstartedtheammoniabusinessinNorthwich,Cheshirein 1873andthisfirmwasoneoftheprecursorsofI.C.I.,M.R.Fox,(1987):3435W.J. Reader,(1970):111:L.F.Haber,(1971):101,157,189. 239 J.T.Brunner,OrganisingChemicalIndustryChemist&Druggist88.3(27May 1916):3941.RegardingdebatesonImperialCollegethereareextensiverecordsatthe archiveincludingthoseofF.H.Carr. 240 C.A.Hill,T.D.Morson,ManufactureofFinechemicalsinRelationtoBritish IndustryandD.B.Dott,VegetableAlkaloidsHowtheWarhasAffectedTheir ProductionBritishandColonialPharmacist(June1915)4367,(quote)in2130B/CARR cuttingsIV:3,ArchivesatImperialCollege.
181
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sulphate,chlorsulphonicacid,carbonylchloride,phenylhydrazine, acetoaceticether,phosphoruspentachlorideetc.eventhoughon accountofthequantitiesatfirstdemandedsuchundertakingscould onlyberegardedasbusinesspropositionsonlybythose observerswhosemotivesaretemperedbytheneedsofthechemical 241 industryasawhole. Heconcluded: whetherornotthemanufactureofsyntheticdrugswilldeveloptoa largeindustryabletoholditsownintheworldsmarketswillbe determinedbytedyeindustry.Withalargedyeindustrythesupplyof intermediateswouldbeassured.Attheconclusionofthewarthenew cokeovenplantsthathavebeenestablished,will,wehope,beableto 242 supplyimmensequantitiesofbyproducts. However,oneoftheperceivedproblemsofcollaborativeprojectsasawartimemeasure wasthatindividualsfromrivalfirmswouldbegrantedaccesstoeachotherscompany secretsbecausetheMinistryofMunitionshadpowers,torequireanypersonto
243 communicatetoaperson...allknowledgeof hisprocess. Becauseofthisandbecause
oftheirexperienceofhavingstaffpoached,BurroughsWellcomerefusedtosend
244 representativestomanycommittees,despiteanapproachbyMoulton. Thusthe
F.H.Carr,SyntheticOrganicDrugs:TheirManufactureasAffectedbytheWar Chemist&Druggist88.4(29July1916):77879. 242 F.H.Carr,(29July1916):778. 243 TradeMarksAppliedForChemist&Druggist,88.5(4November1916):44. 244 AlthoughOBriendidserveonacommitteeregardingvaccineproduction:H.J. Parish,WF:85/20:20chapter3. 245 UnderSirRobertMorantthiscommitteeconsistedofEdmundWhite,Chairmanof thePharmaceuticalSociety.C.A.Hill,andJohnC.UmneywhotogetherwroteThe EssentialOilsoftheB.P.Chemist&Druggist(12February1919):271.Bothcontributed totheB.P.of1914.Chemist&Druggist85.2(3October1914):30,4958.Italso includedW.J.U.WoolcockhewasSecretaryoftheBritishPharmaceuticalConference
182
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
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becausesomefirmstookadvantagebyonlyproducingthemostprofitablelines,whilethe
246 aimwastoensurethatallessentialdrugsweremade. TheABCMlobbiedthe
TheABCMrepresentedamixedgroup,includingtheheavychemicalmanufacturing companies,andthereweresignsitwillbeconfinedtorepresentativesofthelarger
250 firms. ThemaincommitteeincludedMr.C.A.HillofBritishDrugHousesand
in1913.NationalInsuranceActChemist&Druggist(5July1913):5558BernardM. Allen,SirRobertMorant:aGreatPublicServant(London:MacMillan,1934). 246 ThePriceofDrugsBritishMedicalJournal (3April1916):420A.J.Taylor (1971):40ExcessProfitsActChemist&Druggist(27April1918):43. 247 W.J.Reader,(1970):256,321,4512,476. 248 ReportsoftheAlienPropertyCustodianJournalofIndustrialChemistry (April 1919):355. 249 ImportedSyntheticDrugsBritishMedicalJournal (10June1916):828,868. 250 BritishChemicalIndustry Chemist&Druggist(19June1915):467.
183
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
184
rallyingcallforprotectionoftheinfantindustryinhis1916speechtotheSCIwhenhe stated: asofthefuturesomeformofprotectionisofvitalnecessitytoour chemicalindustry,forwithoutitanythingaccomplishedwillbe demolishedrapidlyandcompletelybycompetitionfromabroad...no opportunityshouldbelostofimpressinguponthenationanditsrulers thatthepossessionofapowerfulandselfcontainedchemicalindustry hadthesamedegreeofimportanceasthegreatengineeringindustry hadproventobe...wemustasanationdosomethingtosafeguard 255 newindustries. HewasconcernedthatGermancompetitionwilladopteveryskilfulmanoeuvretocombat newdevelopmentsinthiscountrysuchascharginghighpricesforintermediateproducts,
251
ABCMChemist&Druggist88.3(1916):37,41,(665,683,)ABCMCarrand HowardElectedChemist&Druggist88.5(18November1916):36. 252 J.DavidsonPratt,TheEconomicsoftheFineChemicalIndustryChemistryand Industry (20January1951):38. 253 L.F.Haber(1971):234. 254 BritishChemicalIndustryChemist&Druggist88.4(22July1916):799800. 255 F.H.Carr,SyntheticOrganicDrugs:theirManufactureasAffectedbytheWar Chemist&Druggist(29July1916):778.TranscriptofapapergiventotheSCIon20July 1916.
184
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185
offeringlowtermsforfinishedproducts,orlongperiodcontracts,systematicdumping
256 etc.
proposedexclusionofallGermanproductsandwasnotallowingGermanmanufacturingin
259 France,andRussiawasconsideringthesame.
CarrconsideredthatinordertounderstandtheseproblemstheBoardofTrade
260 neededsomebodyfromthechemicaltradesonitsReconstructioncommittee. Initially
theBoardofTradeexcludedABCMrepresentativesuntiltheyrecognisedtheirgrowing contributiontochemicalmanufacture,asthegroup,whichwasthemostrepresentative...at
261 presentinexistenceinthecountry.
Runcimanscommitteeseventuallyagreedtoprotection,notonlyinchemicals,but alsofortextiles,ironandsteel,andengineering.AttheBritishAssociationmeetingin
262 September1916,Prof.G.G.Henderson presentedapapertothechemicalsection
256
257
Ibid. Ibid. 258 Ibid 259 SirWilliamRamsay,SocietyoftheChemicalIndustryChemist&Druggist86.2 (6March1915):53. 260 TheMinistryofReconstructioncommitteewassetupaddressthepotentialpostwar tradewars,andsocialandeconomicproblemsoffacingastrongGermanyandcentral European'Zollverein'orcustomsunion.A.J.Taylor,(1971):93. 261 Nature102(1918)no.2562:2723 Nature103(1919)no.2568:383. ChemicalTradeJournal 63(1918)no.1647:38. 262 SirJamesIrvine,J.L.Simonsen,GeorgeGeraldHendersonObituaryNoticesof FellowsoftheRoyalSociety (1944)4:491502.
185
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
186
4.9.2TheDepartmentofScientificandIndustrialResearchandtheTrainingof Chemists. WhenRaphaelMeldolawrotetoTheTimeson20January1915,hismainworry abouttheproposedcreationofBritishDyesLtd.wasthatthedirectorshipsuggesteddid notincludearepresentativeofscientificchemistrytheninJulyofthatyearhewasinvited tochairtheAdvisoryCouncilofBritishDyes.MeldolaurgedtheBoardofTradetosetup acommitteeregardingchemicalsupplyandproposedaschemefortheorganisationand developmentofScientificandIndustrialresearch.Howeverhediedon15November1915 beforeseeingthistocompletion. TheRoyalSociety,theBritishScienceGuild,theSocietyoftheChemicalIndustry, andtheInstituteofChemistryacknowledgedtheproblemofalackofsufficientscientific education.TheAdvisoryCounciloftheCommitteeofthePrivyCouncilwasformedin July1915andtheDepartmentofScientificandIndustrialResearch(DSIR)inDecember
263
186
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
187
groupswastoincreasetechnicalexpertiserelatedtoscienceandparticularlychemistryand itsapplicationtoindustry.The(DSIR)calledfor: alargelyincreasedsupplyofcompetentresearcherssecondlya heartyspiritofcooperatingamongallconcerned,menofscience, menofbusiness,workingmen,professionalmenandscientific societies,universitiesandtechnicalcolleges,localauthoritiesand 267 Governmentdepartments. Aparticularemphasiswasplacedonindustriesthathadbecomelocalisedabroadand particularlyinGermanyandconcernsaboutthedifficultiestobefacedpostwarunless
268 269 therewasgrowthandorganisationofscientificresources. GeorgeBeilby ,amember
ofthePrivyCouncilstated:
265
SirHaroldMelville,TheDSIR:DoesitPayOff? (London:GeorgeAllen&Unwin, 1961):26IanVarcoe,Scientists,GovernmentandOrganisedResearch:theEarlyHistory oftheD.S.I.R.191416Minerva8(1976):192217I.Varcoe,OrganisingforSciencein Britain:aCaseStudyoftheDepartmentforScientificandIndustrialResearch(DSIR) 191664(Oxford:UniversityPress,1974)R.McLeod,E.K.Andrews,TheOriginsof theD.S.I.R.ReflectionsonMenandIdeas,19156PublicAdministration 48(1970): 2348E.Hutchinson,ScientistsasanInferiorClass:TheEarlyYearsoftheD.S.I.R. Minerva8(1970):396411J.D.Bernal,ScienceinHistory (London:C.A.Watts&Co., 1965)C.E.K.Mees,ThePathofScience(Chichester:JohnWiley,1946)J.Jewkes,D. Sawers,R.Stillerman,TheSourcesofInvention (London:MacMillan,1955)A.C. Seward(ed.),ScienceandtheNation (Cambridge:CambridgeUniversityPress,1971)A. Marwick,(1965)especiallychapter7.
266
ReportoftheCommitteeonthePositionofNaturalScienceintheEducational SystemofGreatBritain.(London:HMSO,1918),Cd9011:53,57,64DavidLayton, EducationinInstitutionalisedSocietiesin AHistoryofTechnology,vol.1,TrevorI. Williams(ed.),(Oxford:ClarendonPress,1978)IanVarcoe,CooperativeResearch AssociationsinBritishIndustryMinerva19(1981):43363E.F.Armstrong,Chemistry inthe20thCentury:anAccountoftheAchievementandPresentStateofKnowledgeof ChemicalScience(London:ErnestBenn,1924):88.V.E.Coslett(ed.),Scientific ResearchinUniversitiesandIndustry.AReportontheConditionsinGreatBritain (London:AssociationofUniversityTeachers,1955). 267 R.C.Cochrane,MeasuresforProgress(Washington:NationalBureauofStandards, 1966):231,559. 268 Ibid. 269 Beilbyhadbeeninvolvedinthecyanidebusinessandpatentedamethodofmaking potassiumcyanideusedbyCasselJudySlinn,(1984):61.
187
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
188
Theplaceofchemistryinthenationallifehasbeenfarmore importantthanthemajorityofeducatedpeoplehaveimagined,and thisplacebidsfairtobecomeofvastlyincreasedimportanceinthe nearfuture.Thespecialmessageforparentsandteachersis, therefore,thattrainedchemistswill,inthenearfuture,beinincreased 270 demandforindustrialandofficialoppositions. TheGovernmentrecognisedthat:aspecialneedexistsatthepresenttimefornew machineryandforadditionalstateassistanceinordertopromoteandorganisescientific researchwithaview,especiallytoitsapplicationtotradeandindustry.TheHaldane committee,whichwasestablishedin1908,wasproposingtoincreasethefundingof scientificresearchandtrainingofchemistsaftertheeffortsoftheBritishAssociationfor
271 theAdvancementofScience.
AttheSocietyof theChemicalIndustrymeetingin1916furtherpointsaddressedby FrancisCarrwereeducationandtrainingandheidentifiedtwoclassesofworkers:technical andexpertoperatives: Thefirst(class)consistsofresourcefulwelltrainedchemists directingonthespot,operativesofthesecond.Hereferredtothe specialqualificationsofthesefirstclassmenandsaidthatinsynthetic chemicalmanufactureandaboveallotherbranchesofchemical manufacturemenofthiskindcombiningbusinessandscienceare 272 indispensable. Hesuggestedoneormoretechnologicalcolleges,withmanufacturingcapabilitiessothat chemistscouldspendaconsiderabletimeproducingsyntheticdrugsunderexpertguidance, focusingonproducingthoserequiredinsmallquantitiesofthesortnotcosteffectivefor Britishindustrytoproduce. Thecollegewouldhavealargepermanentstaffandwouldbeconductedalongstrict businesslines.Theaimwouldbetocreaterealisticmanufacturingconditionswhere studentscouldworkinchemical,physicalandengineeringlaboratories,withdrawing rooms,joinersandfittersshopsandaplantgeneratingsteam,gasandelectricity,allof whichcouldbemeteredandexpressedquantitativelysothatstudentsgainedthevalueof
270
188
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
189
rawmaterials,yieldsofreactions,theheatandpowerabsorbed,thetimeandlabour expended.Studentswouldbegivenacommercialperspectiveandwouldundergo instructioninaccountancyandcosting.Studentswouldspendtimeintheanalytical laboratoryin whichintermediatesandthefinalproductwereexamined.Theywouldhave instructioninphysicalandelectrochemistry,appliedmathematics,constructionanddesign andpreparationofsteamjoints,chemicalengineering,machinedrawing,repairs,useof specialmachineryandplant,stokingandenginedriving,makingsteamjointsandwood turning.Theseweretheskillsrequiredtorunamodernpharmaceuticalbusinessworks. Thesecondyearwouldcoverengineeringincludingsteamraisingandpowerproduction
273 andanalysisofwasteandfluegases.
drugs.
275
Indoingsotheycreatednewchallengesofhowthemodelwouldbeextended
intopeacetimeandhownewproductsarisingwouldbetested.
4.10TheMRCProposeClinicalTesting
272
Editorial,Science,EducationandGovernmentBritishMedicalJournal (5February 1916):20910. 273 F.H.Carr,SyntheticDrugIndustryChemist&Druggist(9September1916):457. 274 S.M.HArmitage,ThePoliticsofDecontrolofIndustry:BritainandtheUnited States(London:Wadenfeld&Nicholson,1969)P.B.Johnson,LandFitforHeroes:The PlanningofBritishReconstruction19169 (Chicago:ChicagoUniversityPress,1968). 275 A.J.P.Taylor,(1988):45,49,91,176,321,3716,426W.J.Reader,(1970): 132L.F.Haber,(1971):173.
189
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TheMRChadgainedsomeexperienceofclinicalevaluationbyperformingasmall trialofbismuthiodidedoublesaltofemetineatamilitaryhospitalforthetreatmentof
278 amoebicdysenteryandthisbecamethestandardtherapy. Salvarsanwasmorecomplex
276
TheRoyalCommissiononVenerealDiseaseswasappointedinNovember1913with theaimtoinquireintotheprevalenceofvenerealdiseasesintheUnitedKingdom,their effectsuponthehealthofthecommunity,andthemeansbywhichthoseeffectscanbe alleviatedorprevented.(HMSO:Cmnd.8189,1916) 277 RoyalCommissiononVenerealDiseaseRegulationsBritishMedicalJournal (11 March1916):3806. 278 H.H.DaleArchives,RoyalSocietyNIMR,93HD47.13.144. 279 TheManufactureofSalvarsanProductsinEnglandandFranceBritishMedical Journal (10April1915):649BritishMadeSalvarsanBritishMedicalJournal (17April 1915):689690J.E.R.McDonagh,TheManufactureofSalvarsanProductsinEngland andFranceBritishMedicalJournal (17April1915):697J.E.R.McDonagh,D.Watson, TheManufactureofSalvarsanProductsinEnglandandFranceBritishMedicalJournal (24April1915):7423EhrlichsRecentModificationofSalvarsanBritishMedical Journal (24April1915):979TheManufactureofSalvarsanProductsinEnglandand
190
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TheCommitteeventuretourgethatmembersofthemedical professionwouldbeperformingaserviceofnationalimportance,in thepresentemergency,bykeepingaccuraterecordsofcasesinwhich thenewpreparationsareused,andbyplacingsuchrecordsatthe disposalofthecommitteefortheirprivateinformationandguidance. Particularstressmustbelaiduponthedesirabilityofrecordingin everycase,thenameofthepreparationusedandtheserialnumber appliedbythemanufacturertotheparticularbatchemployedtogether withsuchdetailsastodosage,theprecautionstakentoensurepurity ofthewaterusedandfinallytheresultsoftheadministration,bothas regardstherapeuticefficacyandthepresenceorabsenceofspecial 280 incidentalsymptoms. Someauthors,lessconvinced,consideredthateffortstoproducedrugssuchasSalvarsan wouldbebetterspentpreparingT.N.T.(trinitrotoluene)andtheywereconcernedabout
281 toxicityduetothearsenicpresentinSalvarsan. Oneofthearmyphysicians,H.C.
Lucey,basedattheRoyalHerbertHospital,Woolwichwrote:IbelieveKharsivantobe everybitaspotentastheoriginalGermanpreparationintheincidenceofadversereactions
282 cataloguedandthebactericidalpoweroftheblood. TheBritishMedicalAssociation
wereclearlynotconvincedbyBritishmanufacturerswhentheystatedthat:wehavemuch tolearnandalongwaytotravelbeforeourchemistscanputabeautifulpacketofsodium
283 salicylateat3shillingsapoundonthemarket(AstheGermanscould). Salvarsanwas
clearlyimportanttotheArmyandreservesofdrugsatWoolwicheventuallyincluded250
284 milliontablets. TheMRCalsoofferedsupport:
theCommitteeareconfidentthatsofarasthestrictestlaboratory controlscanensureit,theprofessionandthepublicarenowreceiving fromEnglishandFrenchsourcescompoundsfullyuptothestandard 285 ofthebestGermansuppliespreviouslysold. France(26June1915):1087BritishandFrenchSalvarsanProductsBritishMedical Journal (26June1915):1091. 280 TheManufactureofSalvarsanProductsinEnglandandFranceBritishMedical Journal (10April1915):649. 281 TheChemicalConstitutionofCertainProprietaryDrugsBritishMedicalJournal (10July1915):75. 282 H.C.Lucey,RAMC,RoyalHerbertHospital,Woolwich,BritishandFrench SalvarsanProductsBritishMedicalJournal (10July1915):7576. 283 ImportedSyntheticDrugsBritishMedicalJournal (17June1916):868. 284 SirW.G.MacPherson,(1921). 285 ManufactureofSalvarsanProductsInEnglandandFranceBritishMedicalJournal (26June1915):1087.
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Butthissummarisedthekeyissue.MRCargumentswerebasedonlaboratorydatarather thanclinicaloutcomes.WhentheMRCannouncedtheirresultstheywerestrongly supportivefortheBritishmanufacturerseffortstomanufacturesyntheticSalvarsan: theCommitteearesatisfiedthattheproductstestedbiologically undertheirdirectionwerenotinferior,insafetyorinefficacy,tothe originalGermanpreparations.Itmayberemarkedherethatthe satisfactoryresultsofclinicaltrials,aswellastheresultsoflaboratory testsfortoxicity,wereinthehandsoftheCommitteebeforetheissue 286 oftheseproductswasauthorised. H.C.LuceyattheRoyalHerbertHospital,Woolwichrecordedindetailtheeffectsofa
287 further600injectionsofKharsivanin1916. StudiesofKharsivanandGalylwere
reportedfromFrance.Of96cases,84hadnoreactions,11onlyslightandonehada
288 significantreaction.
Andyettherewereconcernsaboutsafetyandtherewasasecondenquiryin
289 Germanyin1917onthesafetyofSalvarsan. Col.L.W.Harrison,oftheRoyal Army
MedicalCorps.(RAMC)reviewedover40,000casestreatedintheArmyandbelieved
290 thatKharsivan,SalvarsanandArsenobenzolwereequallyefficaciousandsafe. Major
LloydJones,(RAMC)performedtestson200patients.Of1,320injections,only37%did
291 notgiveanadversereaction. Haslarhospitalproduceddataon1833injectionsof 292 arsenicals,allofBritishmanufacture. Itwasagainstthisbackgroundofcontinued
286
J.E.R.McDonagh,ManufactureofSalvarsanProductsinEnglandandFrance BritishMedicalJournal (10April1915):64950. 287 H.C.Lucey,TheTherapeuticandReactionEffectsofKharsivanBritishMedical Journal (29April1916):6148. 288 TreatmentofSyphilisBritishMedicalJournal (1January1916):16. 289 MRCReportoftheSalvarsanCommittee66II.ToxicEffectsFollowingthe EmploymentofArsenobenzolPreparations(London:HMSO,1922). 290 ToxicEffectsofArsenobenzolPreparationsMRCSpecialReportSeries41 SpecialCommissionupontheManufacture,BiologicalTestingofSalvarsanandits Substitutes,MRCSpecialReportSeries44(1919):35. 291 JohnAdam,SalvarsanTreatmentofSyphilisBritishMedicalJournal (17February 1917):234anotherreportofover200injectionsgaveamorefavourablereaction.The ProphylaxisofVenerealDiseasesBritishMedicalJournal (17February1917):2434. 292 SirArthurMay,MedicineandtheSeaAffairBritishMedicalJournal (28April 1917):5335ofthese1522werekharsivan,55Galyland256arsenobenzolbillon.
192
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inPharmacologyatOxfordandDr.Turner,ReaderinMorbidAnatomyattheUniversityof Londontotestthechronicorultimateeffects[ofSalvarsan]inexperimentson
294 animals.
TheMRCrecognisedthesignificanceoftheproductionofSalvarsanbyBritish firmsandtheyemphasisedtheirownpartinorganisingtheeffort: Inthisundertaking,intheemergencycreatedbythewar,adutyoutsidethe strictlimitsofmedicalresearch,thecommitteearesatisfiedthattheyhave assisted,notonlyinmeetinganimmediatenationalneed,butinfoundingan industrywhichwillbeofincreasingimportancetothepracticeofmedicine andtothehealth ofthecommunityasprogressiveeffectisgiventothe 296 recommendationsoftheRoyalCommissiononVenerealDiseases. Thus,alladvertisingbypatentmedicinemanufacturersforthisdiseasewasbannedand therapyhadtobeadministeredbyaGeneralPractitioner,sodiscouragingconcealment, continuedspreadofdiseaseandselftreatmentastrongendorsementforethicalmedicines
297 overpatentmedicines. TheVenerealDiseasesBillwaspassedon25May1917,and
293
MajorFrederickAndrewes(Chairman,PathologyLaboratory,StBartholomew's), SurgeonGeneralHumphreyRollestonofCambridge,ColonelL.W.HarrisonandMajorC. J.White,bothoftheRAMC,MilitaryHospital,RochesterRow,F.J.H.Coutts,Professor W.Bulloch,ofTheLondonHospital,J.W.McNee,UniversityCollegeMedicalSchool, andDr.H.H.Dale.MRCSalvarsanCommitteeMinutes,MB22,(14February1918):1. 294 MRCSalvarsanCommitteeMinutesMB22(14February1918):1. 295 W.S.Feldberg,HenryHallettDale18751968 BiographicalMemoirsof FellowsoftheRoyalSociety 16(1970):107. 296 th 5 MRCAnnualReportin BritishMedicalJournal (14January1922):74. 297 TheProphylaxisofVenerealDiseasesBritishMedicalJournal (24February1917): 27881WilliamOsler,TheCampaignagainstVenerealDiseaseBritishMedicalJournal (26May1917):6946.
193
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centreswereestablishedacrossthecountrywherepeoplecouldbediagnosedandtreated
298 freeofcharge.Itbecameacriminaloffenceknowinglytocommunicatethedisease.
Havingrecommendedcontrolledtherapywitharsenicalsitbecameincumbentonthe GovernmenttoensurethatSalvarsanandsimilardrugswereusedsafely.
managerofBurroughsWellcome,H.A.D.Jowettdescribedtheprecautionstakeninthe
303 synthesisof Salvarsanfromarsenic. Theprocessinvolvedacomplexseriesof
reactions,purifications,analyses,crystallisations,andprecipitations.Thefinalproducthad tobeprotectedfromoxygenbysealingvialsundersulphurdioxidegas.Itwasthen
298
CriminalLawAmendmentBillTheTreatmentofVenerealDiseasesBritish MedicalJournal (17March1917):3723. 300 299 InitialmembershipwasthesurgeonH MRCSalvarsanCommitteeMinutes MB22,(undated,February1918):2. 301 MRCSalvarsanCommitteeMinutesMB22,(14February1918):2. 302 MRCSalvarsanCommitteeMinutesMB22,(5March1918):3. 303 MRCSalvarsanCommitteeMinutesMB22,(22March1918):5.
194
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
195
assayedbothchemicallyandinabiologicaltest.TheMRCconcluded:theproductseems
304 uniform,theonlymarkedvariationisastotheresultofthebiologicaltest.
theproductfromair,buttheirpharmacistGillingfeltthiswassuitableiftheydidnottake
306 toolonginthepreparationandaslongasmaterialsremaineddry.
304 305
MRCSalvarsanCommitteeMinutesMB22,(22March1918):5. FordetailsontheagreementbetweenPoulencandMay&BakerseeJudySlinn, (1984)MRCSalvarsanCommitteeMinutesMB22,(11March1918):4. 306 MRCSalvarsanCommitteeMinutesMB22,(19February1919):25. 307 MRCSalvarsanCommitteeMinutesMB22,(5March1919):27the novarsenobenzolpreparation,glucarsenolwasfromtheAngloFrenchDrugCompany. 308 MRCSalvarsanCommitteeMinutesMB22,(22March1919):30.
195
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
196
HenryDaleinvestigatedNovarsenobillonandNeokharsivaninrabbits,in
313 comparisonwiththeoriginalGermanNeosalvarsan. Allthreegavesimilarresultsand 314 heconcludedonlythattherewasaninterestingcomparativefatality. TheCommittee
wantedtocomparetheBritishandFrenchdrugswithCanadianandGermandrugs,which
315 hadbeenassociatedwithjaundice. However,intryingtoobtaindatafromArmycentres,
309
MRCSalvarsanCommitteeMinutesMB22,(26March1919):31TheAngloFrench drugcompanyappliedtotheM.R.C.toimportGalylwithalowerarseniccontent. 310 G.E.Pearson,(1936),TypescriptWF:88/24:41d:12. 311 MRCSalvarsanCommitteeMinutesMB22,(8October1919):50. 312 MRCSalvarsanCommitteeMinutesMB22,(1May1918):10. 313 MRCSalvarsanCommitteeMinutesMB22,(17April1918):9. 314 MRCSalvarsanCommitteeMinutesMB22,(18May1918):11. 315 MRCSalvarsanCommitteeMinutesMB22,(31May1918):12(4October1918): 20(4December1918):21(30April1919):37. 316 MRCSalvarsanCommitteeMinutesMB22,(15May1918):11(17July1918):16.
196
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
197
317 strictguidelinestonewproductsemergingfromGermanysuchassilverSalvarsan.
arisingfromdeathsandadverseeffectssuchasdermatitisandjaundiceinBritishandallied
319 hospitals,butthesecontinuedtobedifficulttoquantifyunderconditionsofwar. Inorder
togainwiderexperienceDalecorrespondedwithDrReidHuntofHarvardUniversityin Bostonandcomparedhisresultsinrats,usinglowerdoseswithhisownstudiesin
320 rabbits.
summarisingtheArmyexperiencewithSalvarsanwasunabletoprovideanycomparative
322 data,thoughhereportedthatthearmyinFrancewasalreadyusingSilverSalvarsan.
Inprivate,theSalvarsanCommitteeacknowledgedthatitwasimpossibleto properlydefinetherelativetherapeuticvaluefromarmyreturns,thoughthedatadidenable
317
MRCSalvarsanCommitteeMinutesMB22,(18December1918):22. MRCSalvarsanCommitteeMinutesMB22,(18December1918):22. 319 MRC.SalvarsanCommitteeMinutesMB22,(14February1918):1 MRCReportof theSalvarsanCommittee66II.ToxicEffectsFollowingtheEmploymentof ArsenobenzolPreparations(London:H.M.S.O.,1922)TheToxicEffectsofSalvarsan, BritishMedical Journal (18December1920):945 MRCSpecialReportSeries41(1917) ToxicEffectsofArsenobenzolPreparationsinSurgeryII,aClinicalStudyoftheToxic ReactionsFollowingtheIntravenousAdministrationof914Lt.ColR.J.G.Parnell,P. Fildes,SpecialCommissionUpontheManufacture,BiologicalTestingetc.ofSalvarsan anditsSubstitutesMRCSpecialReportSeries44(1919).
318
320
197
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
198
Salvarsan,itwasonlynaturalthattheMRCSalvarsanCommitteewouldbeasked searchingquestions.WalterMorleyFletcheransweredonequerywiththeopinionthat probablythesafestisHoechst'sNeosalvarsan('914')bysyringe.Healsostatedthat: theCommitteehadcometotheconclusionthattherewasno appreciabledifferencebetweenthevariousneosalvarsanpreparations andthosefromBritain,FranceandCanadaseemequallyefficacious withtheoriginalGermanNeosalvarsan,andnotmorelikelytobe 324 followedbyilleffects. Prof.SimsWoodheadinvestigatedadversereports,andProf.W.Bullochwasaskedto collectfurtherstatisticson'606'and'914'attheLondonHospital.IncontrasttoFletcher's publicsupportforBritishdrugs,thenextmeetingoftheCommitteeagreedthatitwasnot evenpossibletomakean accuratestatementaboutthenumbersofpatientstreatedwith eachpreparation,letalonethepercentagesuccessrate,withoutwhichno'statistical'
325 comparisonswerepossible. TheMRCagaintriedtodistinguishwhatthereportsof
efficacyofSalvarsanfromtheirdiverse,incomplete,andprimarilyarmysources.Instead theycouldonlyreportonstandardisednomenclatureandchemicaltestingofthevarious
327 preparationstocontroltheirsale. Giventheexigenciesoftheperiod,itisperhapsnot
surprisingthatreliableretrospectivelycollecteddatawasdifficulttoobtain.Therewere twoissues,thelackofconsistentdatarecordformsandthewayinwhichcontemporary
30.
326 327
198
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
199
theMRCwereunabletoimposeamoresystematicapproachontheorganisationand collectionofmedicaldatathattheywanted.Theyroutinelytestedbatchessubmittedby Britishfirms,agreedlicensesforimportingfirmsandsearchedoutforeignbatchesthat wereobviouslyinadequateorunsafe. Asaresultoftheirproblems,theCommitteewishedtomakethecontrolofthese substancescompulsory.Both'606' and'914'cameundertheheadingofarsenicandits medicinalpreparationsinpartIofthePharmacyActof1908andhadtobelabelledas 'Poison'.HoweveroneMemberofParliament,inanswertoquestionsasked: Itwasnotclearwhoshouldtakeactiontoseetoenforcementofthe requirementsorinwhatwaytheseobligationswouldassistin obtainingpropertestsorwouldpreventthesaleofpreparationsnot conforming.Itmightbedesirabletoempowersomecompetentbody 329 toschedulecertaindrugssothatdefinitetestscouldbeenforced. ThiswasthefirstsuggestionofanationaldruglicensingsystemandtheMRCweretobe responsibleforrecommendinglicenses. InFebruary1918,theCommitteefirstdiscussedthepossibilityofFrankPyman, helpingthemwithsafetystudies.PymanhaddepartedBurroughsWellcometotakeupthe postofProfessorofTechnologicalChemistryintheUniversityofManchesterandHeadof theDepartmentofAppliedChemistry.Pymanwaswillingtoperformfurthertestson GermansubstancesonbehalfoftheMRC,butaslateasFebruary1919hislaboratorywas
330 notyetinorder.
328
SeeU.Troehler,QuantificationinBritishMedicineandSurgery17501830,with SpecialReferencetoitsIntroductionintoTherapeutics.(UniversityofLondon:PhD Thesis,1978). 329 MRCSalvarsanCommitteeMinutesMB22,(11April1919):35. 330 MRCSalvarsanCommitteeMinutesMB22,(11April1919):35.Thelaboratory referredtomusthavebeenintheDepartmentofAppliedChemistryintheCollegeof TechnologyinManchesterwherehewasappointedProfessorbeginningon1March1919: H.King.FrankLeePymanBiographicalMemoirsofFellowsoftheRoyalSociety 4 (1944):687.
199
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
200
KingstudiedtheimpuritiescontainedincommercialpreparationsofSalvarsanand
331 identifiedthemainproblematiccomponentwhichwastwiceastoxicasSalvarsanitself.
SalvarsanCommitteeconsideredthatimportationofforeigndrugswithouttestingmight leadtorisktothepublicandunfaircompetitionwithBritishmanufacturerswhoare
333 compelledtosubmittheirproductsfortesting. Ifforeignpreparationsweretobe
toadmitthatanimaltestsfailedtopredictforproblemsinclinicaluse,andthisrecognition
335 ledtheMRCtoconcludethattheydefinitelyneededcomparativeclinicalresults.
Fildes'spapersummarisingarmydatawasstillonlyindraftforminJuly1919and hisfindingswerequitegeneral:hestressedhewasprovidingonlyresultsandnotaguideto
336 therapy. Incontrasttothepatchyandlargelyincompletedataavailable,theCommittee
hadquitegrandioseplansforanalysiswiththeillnesstobeclassedintooneof12groups, withresultssubdividedbythebrandofdrugs(therewerearound13),thenumberof
331
MRCSalvarsanCommitteeMinutesMB22,(11April1919):35H.King, DerivativesofSulphurinCommercialSalvarsanpartsIandII.J.ChemicalSociety 119 (1921):1107,1415. 332 MRCSalvarsanCommitteeMinutesMB22,(30April1919):37(28May1919): 40. 333 MRCSalvarsanCommitteeMinutesMB22,(4February1920):52. 334 MRCSalvarsanCommitteeMinutesMB22,(2July1919):43. 335 MRCSalvarsanCommitteeMinutesMB22,(8July1919):44. 336 MRCSalvarsanCommitteeMinutesMB22,(23July1919):46.
200
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
201
injections,thetotaldose,theamountofmercurycontained,toxiceffects,theirduration,
337 andclinicalresults.
WiththeincreasingworkloadDalerequiredareliableassistantandoncompletionofhis medicalstudiesJoshuaH.Burn,anotherexBurroughsWellcomeresearcherrejoinedhim
339 attheNIMRon1September1920andtheywerelatersupportedbytwotechnicians.
337
MRCSalvarsancommitteeMinutesMB22,(26November1919):51MRCReport ontheultimateresultsofthetreatmentofsyphiliswitharsenicalcompounds(1919)(2): 867. 338 J.AustokerandL.Bryder,TheNationalInstituteforMedicalResearchandRelated ActivitiesoftheMRCinJ.AustokerandL.Bryder(eds.),(1989):3557. 339 MRCMinutesII,(7July1920):72.Hebecameapermanentmemberfrom1July 1921at500risingby25p.a.to750A.N.RichardsandDaleoninsulinandhistamine alsoE.Buelbring,J.M.Walker,J.H.Burn,(1981):50DrHinestayedfor6months thenwenttoSt.BartstobereplacedbyMrH.C.Sayer,MRCMinutesII,(18March 1921):38(22July1921):127. 340 MRCSalvarsanCommitteeMinutesMB22,(10March1920):54. 341 MRCSalvarsanCommitteeMinutesMB22,(19May1920):56.
201
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
202
InmarkedcontrasttotheapparentaccuracyofreportinginGermany,itwas impossiblewiththeBritishdatatoclassifyeventheadministrationmethodthoughthere
343 wasanimpressionthatarsenobillonwaslosingitseffectiveness. Italsobecameclearthat 344 thereweresignificantfailingsinthefollowupofpatients. Anyclinicalsuspicionsthat
efficacywasdecreasingpresentedadilemmafortheMRCaftertheyhadsovigorously
345 supportedtheBritishdrugs. FurtherconcernsabouttheefficacyofBritishDrugscame
afterDale'sanimalexperimentsin1921,whichshowedMay&Bakers NovarsenobenzolbillonandBurroughsWellcomesNeokharsivanwerelesseffectivethan
346 BayersNeosalvarsan. TheyquestionedPearsonandJowettofBurroughsWellcome,
342 343
MRCSalvarsanCommitteeMinutesMB22,(21July1920):59. MRCSalvarsanCommitteeMinutesMB22,(29September1920):61. 344 MRCSalvarsanCommitteeMinutesMB22,(19January1921):64. 345 MRCSalvarsanCommitteeMinutesMB22,(1December1920):63. 346 MRCSalvarsanCommitteeMinutesMB22,(18February1921):67. 347 MRCSalvarsanCommitteeMinutesMB22(3March1921):69RichardBlenkinsopp wastheeldestsonofWilliamwhodiedin1916whowasoneofseveralBlenkinsoppsthat hadmanagedthefirmsinceanewpartnershiphadbeenestablishedin1876.Richardtrained inchemistryattheCity&GuildsCollegeinKensingtonfrom18981900:JudySlinn, (1984):8231,86,91,94.
202
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
203
Octoberof1921therewasafurtherapplicationforsulpharsenol,whichthereforehadto
349 undergoDale'sanimalexperimentsforapproval.
preparationsweremoreefficaciousthananyothertreatment.Deathsarefaroutweighedby
351 those,whichwouldoccurwithothermethods. Oneofthereportsprincipal
348 349
MRCSalvarsanCommitteeMinutesMB22,(30June1921):79. MRCSalvarsanCommitteeMinutesMB22,(6October1921):89. 350 P.Fildes,R.J.G.Parnell,AClinicalStudyoftheToxicEffects,whichFollowthe IntravenousAdministrationof'914':MRCSpecialReportSeries41Reportofthe SalvarsanCommittee(London:HMSO,1922)MRCSalvarsanCommitteeII(1922) ToxicEffectsFollowingtheEmploymentofArsenobenzolPreparations:Reportofthe SalvarsanCommitteeBritishMedicalJournal (29July1922):184MRCMinutesII,(17 November1922):383. 351 ToxicEffectsFollowingtheEmploymentofArsenobenzolPreparations:Reportof theSalvarsanCommitteeBritishMedicalJournal (29July1922):184. 352 Ibid.
203
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
204
Thenalongcameanotherthornychallenge.J.E.R.McDonaghwasaLondon physicianwithyearsofexperienceintreatingsyphiliscaseswithSalvarsanandsimilar
354 drugs wemethimpreviouslyasoneofthedoctorsunconvincedbytheMRCthatthe
BritishsubstituteswereasgoodastheirGermanoriginals.InreplytotheSecretaryofthe NIMR,McDonaghexplainedthathehadperformedexperimentsandreadallofthe literature,includingpatents.HeexplainedhisconcernsaboutcomparingBritishand Germanpreparations:becausetheyarechemicallyidenticalitdoesnotfollowthattheyare similarinotherrespectshegavetheexamplethatsyntheticsalicylicacidlooksandacts differentlytoextractsandthatadrenalinandsuprareninarediametricallyopposed.Healso explainedthatthepatentswerewritteninsuchamannerastodeceivesohowcould Britishfirmsbesuretheypreparedthedruginthesameway?Heobservedthatthe SalvarsanproducedbythetwoBritishfirmshadalowyield,andthissuggestedto McDonaghalesscompletelinkage.HecontendedthattheGermandrugsproducedafter 1912wereactuallyofbetterqualitythanwhenthepatentswerewritten.Hedismissedthe MRCbiologicalcontrolsasvaluelessanimalswerenotassensitiveasman.Furthermore, hearguedthatthetoxiceffectwasverymuchgreaterincatscomparedtodogs.Hewent on: IamfairlyoftheopinionfromtheseveraltoxiceffectsIhaveseen followingtheuseofthenewproductsthatthesuccessfulmanufacture hasnotbeensolvedandthatthemedicalprofessionwouldbewell 355 advisedtoawaitthereportsofcliniciansbeforeusingtheproduct. McDonaghsstarkcriticismawakenedaflurryofcorrespondenceandeditorialcommentin theBritishMedicalJournalincludingarebuttalhedoesnotconvinceusthattheyare
353
MRCMinutesII,(28February1921):28(17November1922):383.
354
J.E.R.McDonagh,SalvarsaninSyphilisandAlliedDiseases(London:Hodder& Stoughton,1912).
204
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
205
wellfounded.NobodyunderstoodwhatMcDonaghmeantwhenhewrotebyhis referencestoincompletelinkagesandcolloidalarsenic.TheMRCconcededthatSalvarsan shouldbehighlyreducedbuttheydisagreedthattherewasadifferencebetweennaturaland syntheticsalicylicacidorbetweenadrenalinandsyntheticSuprarenin. TocountertheseargumentsMcDonaghgaveanevenmoretechnicalexplanationas towhyhebelievedtheBritishproductspreparedinadifferentwaymightbemoretoxic. HepointedoutthattheamountofreductionrequiredwasnotspecifiedintheGerman patentsandchallengedtheMRCwhydidEhrlichdeemitnecessarytohavethereportsof certainmedicalmenbeforeallowingthedrugtocomeuponthemarket.Ehrlichtookthe samepositionin1912withneosalvarsan,althoughhewasfullyawareonapriorigrounds thatthepreparationwaslesstoxicthenSalvarsan.FromhisownexperienceMcDonagh reported6casesofexfoliativedermatitisand2casesofjaundicetreatedwiththe BurroughsWellcomeKharsivan.Onediedandthreelostalloftheirhairandallcaseshad hyperkeratosisofthenails.Nonehadmorethan2injectionsandtwohadonlyone injection.Onehaddermatitisonlyaweekafterinjection.In contrasthearguedthathehad giventhousandsofinjectionsofGermanproductsinupto16dosesandhadonlyeverseen
356 onecaseofdermatitisexfoliate. ThisroundofcorrespondenceintheBritishMedical
355
J.E.R.McDonagh,TheManufactureofSalvarsanProductsinEnglandand FranceBritishMedicalJournal (17April1915):697. 356 QuotefromJ.E.R.McDonagh,TheManufactureofSalvarsanProductsinEngland andFranceBritishMedicalJournal (17April1915):697furthercorrespondence:J.E.R. McDonagh,DavidWatson,TheManufactureofSalvarsanProductsinEnglandand FranceBritishMedicalJournal (24April1915):7423EditorialcommentBritish MedicalJournal (24April1915):697ParenchymatousSyphilisBritishMedicalJournal (30January1915):198
205
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
206
countrysecureanunbiasedtrial,especiallyifthereissoundexperimentalevidenceinits
357 favour.
357
J.E.R.McDonagh,TheRationaleandPracticeofChemotherapyBritishMedical Journal (22April1916):5912and(10June1916):8201.Thisreportcontinuedthe debatethatMcDonaghhadinitiatedinhisfirstpublicationinAprilandwascarriedoutata meetingoftheDermatologicalSectionoftheRoyalSocietyofMedicine. 358 ChemicalIndustryinGermanyandtheUnitedKingdomPharmaceuticalJournal 104(21February1920):162. 359 MajorGeneralSirW.G.MacPherson,HistoryoftheGreatWarvolume1(London: HMSO,1921):1789.
206
PostwarProblems,PatriotismandProtection:
207
However,pharmaceuticalfirmsexpectedsomeformofprotectionfromthereturnof Germancompetitionpostwar,andtheincreasinglyinfluentialAssociationofBritish ChemicalManufacturersledthesecampaigns. Thischapterdealswiththenewchallengesofpeace:ontheonehandexport marketsreopened,ontheotherhandhugewartimesalestothearmedforcesdisappeared. MarketswerefurthercompromisedbytherapidreturntoproductivityoftheGerman industryandthereparationsimposedonGermany.Britishfirmshadtoaddresstheseshort termcompetitiveproblems,whileestablishingthelongertermsupplyofchemicalengineers andclinicaltrialists.Thischapteristhefirstofthreechaptersaddressingtheperiod1921 31bothfromtheindustryandtheMRCperspectiveastheytriedtoexcludeunsafe foreigndrugs,withaprotectionistpolicy therequirementforbiologicallystandardised drugsbytheNIMR.Chapter6addressesthecampaignforclinicaltrials,whichiskept separatebecauseitoccurredinthreemainwavesin1922,1926and1931.Chapter7is thenacasestudyofpostwardevelopmentsandstrategicdiscussionsthattookplacewithin theseframeworksintheScientificandTechnicalCommittee(STC)atBurroughsWellcome 19251939,andthatchaptersetsthesceneandgivesanindustryinsightforchapter8on theestablishmentandworkingoftheTherapeuticTrialsCommitteefrom193139,in whichinsightsfromtheSTCarecontinuedthroughto1939.
FrancisCarrtoSCI,reportedinNottinghamJournal,(October1918)CarrArchives. 2130B/CARRIVPressCuttings:6.
207
PostwarProblems,PatriotismandProtection:
208
PostwarBritishpharmaceuticalfirmslookedtothegovernmentforassistanceand protectionandwerepartiallysuccessful.Theirinitialgains,however,weretemporary, resultinginadownturnintheirbusiness.FortunatelyforBritishfirms,newtherapeutic opportunitiesallowedthemtoexpandinnewdirectionswithoutdirectlyhavingto challengetheincreasingcompetitionfromthemergerofseveralGermanfirms. Nevertheless,Britishfirmscontinuedtomanufacturesomesyntheticdrugsanimportant interwardevelopmentinBritain,whichhasbeenunderestimatedbyhistorians. 5.2PostWarCampaignsfortheProtectionofthePharmaceuticalIndustry. Britishcompaniestookadvantageofmarketsthatopenedupasaresultofthe endingofhostilities,leadingtoaboomperiodof18monthsasexportrestrictionswere removed,butthisonlydelayedtheproblemsofovercapacityofprewarstandarddrugs, aheadofanabrupteconomicdownturn,coincidingwiththeminersstrikeandrising
2 unemployment.
TheendoftheWarrapidlydecreasedthedemandforpainkillers,antiseptics,
3 vaccines,serumsandanaesthetics. ItalsobroughtrenewedcompetitionfromGermanyin 4 theproductionofsyntheticdrugs. EventoremaincompetitivewithMerckandSchering
inproductionofalkaloidsrequiredtechnologicaladvances.Therecommendationsofthe newBritishPharmacopoeiaof1914,onlypartlyimplementedduringtheWar,hadthe
5 effectofreplacingmorealkaloidsbypureactiveprinciples,someofwhichweresynthetic.
ThemarketchallengeswerecompoundedbythesurplusofGermandrugsastheTreatyof
208
PostwarProblems,PatriotismandProtection:
209
VersaillesallowedtheReparationsCommitteetoseizeonehalfofGermanstocksheldon
6 15August1919,and25%ofaveragemonthlyproductionupto1January1925.
ThecampaignforprotectionoftheBritishpharmaceuticalindustryhadbegun duringtheWarwiththefoundationoftheABCMin1916.Justbeforethis,in1915,inhis paperTheManufactureofOrganicDrugsAffectedbytheWarFrancisCarrwrote: Nolongercanwebesatisfiedtobeexternallydependentforsuppliesofvital importance.Itisourdutytoadmitfranklytodaythatsomeform ofprotection isofvitalnecessityduringthecoming10years,whilewedevelopacomplete organisationandrectifyeducationalshortcomings.Withoutthisprotection, whathasalreadybeenachievedwillrapidlyandcompletelybedevastatedby competitionfromabroad.Therecanbenodoubtthattheindustryunprotected 7 wouldbecomethebuttofheavyGermanartillery.
pharmaceuticalfirmsofbetterprovisionofchemicalintermediatesandsolvents,which remainedinlimitedsupplyasaresultofthecontinuedTradingwiththeEnemyActandits
9 Germanequivalent.
InNovemberof1918theBoardofTradeissuedaWhitePaperpromisinggrantsin aidforexpansionandresearch,andthiswasofficiallyannouncedastheCustoms
F.H.Carr,TheBritish&ColonialPharmacist(June1915):4367.
209
PostwarProblems,PatriotismandProtection:
210
ConsolidationAct(Dyestuffs:ProhibitionofImportsProclamation),whichcameintoforce
10 on24February1919tobegintheperiodofprotection. Thiswasatemporarymeasure,
oftaxandfreightcostsandtheyhadagenciesspreadaroundtheworldthatencouragedan
12 extensivecreditsystem. Littlewasknown,however,aboutthewayinwhichGerman
10
11
L.F.Haber,(1971):173W.J.Reader,(1970):280.
F.H.Carr,SyntheticOrganicDrugsChemistandDruggist88.4(29July1916): 77880L.F.Haber,(1971):129.
210
PostwarProblems,PatriotismandProtection:
211
graduatesqualifiedinbiology,pharmacology andchemistrywhowereactivethroughout Germany,dividedinto12districts,eachincludingabout4universities.Eachonereported toLeverkusen,theheadoffice,whichproducedpropaganda.Freesamplesofdrugswere givenout,butnotindiscriminately onlywhenaskedforbydoctorsinterestedinagiven subject. ThevisitstoGermanfactoriesmadetheABCMawareofwhattheywereup against,notonlyregardingdrugsbutalsokeychemicalintermediates.However,therewere nofactoriesintheoccupiedareathatproducedmethanol(bywooddistillation), formaldehydeorformicacid,althoughplantsmakingaceticacid,sodiumacetate,acetic anhydride,chloraceticacidandalcoholwerevisited.ThefactoriesofBayeratElberfeld andMerckatDarmstadtwerejustoutsidetheoccupiedarea.Nevertheless,processesfor theproductionofsalicylicacid,sodiumsalicylate,phenacetin,antipyrin,Salvarsanandits
13
ChemicalIndustryinGermanyandtheUnitedKingdomPharmaceuticalJournal 104(21February1920):162.
14
211
PostwarProblems,PatriotismandProtection:
212
derivatives,lacticacid,chloral,chloroform,cholicacid,opiumalkaloidsandcocaine hydrochloridewereseen.ThesuccessofGermanfirmswasattributedtothescientific equipmentandcontrol,massproduction,efficiencyandsufficiencyofplant,cooperation withothermanufacturersineliminatingwastefulcompetition,whilecontinuingtostimulate theintroductionofnewmethodsandnewproducts.Laboratoriesweredividedinto researchfornewproductsandseparatesectionsfortechnologicalresearchdirectedat improvementandcontrolofprocesses,especiallytheintermediatestagesofnewdrug manufacture.Thelaboratorieshadahighpercentageoftrainedspecialists:atBoehringer, whereopiateswereprepared,10%werechemists.Somemanufacturewasrestrictedto largecapacityfirmsforefficiency.Examplesgivenincludedtheproductionof2tonsper dayofglacialaceticacidatKnapsack,20tonsamonthofantipyrinatHoechst,andthe smallbutspecializedworksofBoehringerproduced4080oz.ofcocainehydrochlorideper day,80tonsamonthoftartaricacidand3tonsadayoflacticacid.Importantbyproducts wererecoveredduringmanufacture:inthecaseofantipyrinthesewerebenzene,sodium bromide,andsodiumacetateandinthecaseofSalvarsanthesewereetherandmethyl
16 alcohol.
16 17
AssociationofBritishChemicalManufacturers,(June1919):101103.
212
PostwarProblems,PatriotismandProtection:
213
AndItisevidentthatBritishchemicalmanufacturerswillnotbeabletocompete
18 successfullywiththeGermanindustryuntilsomesuchcooperationhasbeeneffected.
TheABCMstatedthat: Itisofimportancethatchemicalengineersinthiscountryshoulddevotetheir attentiontothequestionofbeingabletosupplystandardplant,suchastile linedironvesselsasusedforcorrosiveacids,etc.,autoclaves,stills,avarietyof enamelware,earthenwareandfilteringapparatusquicklyandeconomically (and)toequiptheirworksonthese[German]lines,Britishchemical manufacturerswillrequirealargesupplyofwelltrainedchemistswhoarenot 19 onlyablebutwillingtospecialiseintheparticularbranch . Germanfactorieswereinsplendidconditionswithalargeandhighlytrainedforceof employees,andmoreoverwithadditionalopportunitiesforincreasingtheirproductionby utilizingtheextraequipmentaddedforwarmaterialproductiondescribedasa
20 dangerousfactorinthestruggleforcommercialsupremacy. Theclearmessagestaken
homeweretheneedforbetterorganisationoffacilities,andgreaterefficiencyof manufacture.Inshorttherewasasignificantroletobeplayedbychemicalengineers.While Levinsteinreturnedprimarilytodyestuffsmanufacture,FrancisCarr,asoneoftheserare chemicalengineerstookupthegauntlettocampaignforbettertrainingofthisparticular typeofchemistforthepharmaceuticalindustryandthiswillbeaddressedlater,buttowards theendof 1919amoreimmediatechallengethreatenedtheBritishpharmaceutical manufacturers. 5.4TheSankeyJudgmentanditsConsequences. TheprotectioninitiallyaffordedtoBritishmanufacturers,restrictingdyeimports wasfoiledwhenLordJusticeSankeyconfirmedon17December1919thattheDyestuffs ProhibitionofImportsProclamationsetuptoofferprotectionwasillegal.Ithadbeen basedonthe1876CustomsConsolidationAct,whichprohibitedarms,ammunition, gunpowderandanyothergoods.FollowingGermanprotestationsSankeyruledthatlaw didnotgivetheGovernmentthepowertoinvokerestrictiononthetradeofdyes,sohehad
18 19
20
213
PostwarProblems,PatriotismandProtection:
214
21 nooptionbuttoallowGermanimports. Thisjudgmentquicklyledtotheswampingof
22 themarketwithGermandrugs. AttheannualdinneroftheChemicalIndustryClubin
1920,LordMoultonrecounted:Weareatthispresentatacrisisofourhistory.If
23 Englanddoesnotrealisethatitmustbeagreatchemicalnation,itsfutureisgone.
syntheticorganicchemicals,analyticalreagents,allotherfinechemicalsexceptsulphateof
26 quinine,exceptofvegetableoriginsorfromfermentationprocesses.
21
Editorial,TheFineChemicalIndustryBritishMedicalJournal (22January1921):
133.
23
25 26
M.R.Fox,(1987):60.
214
PostwarProblems,PatriotismandProtection:
215
necessityofretainingtheholdonorganicsandalsoreferredtoimportantnew
28 developmentsofnovelhormoneextractssuchasthyroxinin1918
pharmaceuticalsastheSafeguardingofIndustryActin1921,andleviedatariffof33.3% onimports.PearsonofBurroughsWellcomewrotetotheTimesabouthisfirmsapproval oftheSafeguardingofIndustryActthoughtherateoftaxwaslessthanhehadhopedfor. Heclaimed: Theadverseconditionswhichheforesawin1918havesincebecomerealities andthecompetitionfromGermany andothercountriesisnowsuchthatunless theS.C.I.obtainssomeassistanceatsometime,thiscountrywillsinkbackinto theconditionthatitwasinbeforethewarintheeventofanotherwar,this countrywillagainbedependentforoursuppliesofvitalchemicalsonforeign andpossiblyhostilenations. Hereferredtotherecentcaseoftheclosureof14manufacturersofchemicalglasswarein
30 thiscountryand6,000employeesbeinggiven7daysnotice. SamuelRideal,Fellowat
27
NoteshandwrittenbyCarrinpreparationforalectureFilesofFrancisHoward Carr,B.CARR.attheImperialInstitute,London2131B/CARRIII,1920
28
Dyestuffs(ImportRegulation)BillChemist&Druggist93.3(11December1920): 589.
29
IndustrialProtectionChemist&Druggist94.2(9April1921):3334.
215
PostwarProblems,PatriotismandProtection:
216
UCHwroteintheprefacetoBarrowcliffandCarrsbook,OrganicMedicinalChemicals publishedin1921:Creditablethoughtheaccomplishments,Britishmanufactureisnot
31 especiallycosteffective. CarrgaveapresentationinLondoninFebruary1921entitled
situationworsenedin1921whentherewasanationaltradinglossof204,159.After depreciationandtaxrefundsthelosseswereinexcessof1milliononsales,whichwerea
34 quarterofthe1920level.
TheEconomistdescribed1921asoneoftheworstyearsofdepressionsince
35 industrialrevolution. FortheBritishpharmaceuticalindustrytosurviveithadto
InaBritishScienceGuildbookletpreparedin1921Carrwrotethat:
31
S.Rideal,prefaceinM.Barrowcliff,F.H.Carr,IndustrialResearch:Organic MedicinalChemicals(London:Ballire,Tindall&Cox,1921).
32
216
PostwarProblems,PatriotismandProtection:
217
Futureprogressliesinextendingtheuseinourindustry,inclosestpossible relationshipwiththatcarriedoutinacademicinstitutionsandundertheaegisof theM.R.Candsecondlybyfindingemploymentforgreaternumbersof scientificallytrainedstaffsandworkerstowhomisgivenresponsibilityanda 37 livinginterestistheworktheyareperforming. BritainalsosoughtnovelwaysofexcludingGermandrugsthe1921British PharmaceuticalConferenceexecutivecommitteecontinuedtheprocessofdefiningessential drugsandincludedthepharmaceuticalmanufacturers,CharlesHillofBDHandE.T. Neathercott 38 ofSavory&Moore,whiletheresearchsubcommitteeincludedbothFred
39 GambleofAllen&HanburysandCharlesHill. In1922theABCMtookthisastep
further,producingalistofover2,000finechemicalsalreadymanufacturedinBritain,
40 emphasisingthatweoughttobeindependentofforeignsupplies.
StanleyBaldwintookupthiscampaigninOctober1922ashefeltthatBritaincould onlyfightunemploymentwithprotection,whichbecameoneofthekeyelectionissues.
41 However,theelectionofDecember1923wentagainstprotection. Nevertheless,the
GamblesentalettertotheMinisterofHealthaboutthevariableanalysisofprescribed
43 medicines. Bythetimeoftheir1923annualreport,theincreasinglyinfluentialABCM
hadexpandedtorepresent150firms,andproducedadirectoryinFrench,Spanish,
37
F.H.Carr,BritishScienceGuildbooklet,1921intheCarrarchives2130B/CARR, ImperialInstitute,Londonpage77.
38
39 40
41
TheConferencePastandPresentChemist&Druggist99.1(28July1923):129
133.
217
PostwarProblems,PatriotismandProtection:
218
Portuguese,ItalianandGerman.Theyclaimed:Wecanproduceirrefutabledatathatthe KeyIndustrydutyhasbeeninstrumentalinpromotingthedevelopmentofthisimportant
44 keyindustry. Aneditorialin Chemist&Druggistagreedthatmanufacturershadbeen 45 assistedinasmallwaybytheAct.
CharlesHillconsideredthatitwasessentialtomaintaintheActonthestatuteandifitwas droppedorreplacedbysomeotherprotectionwouldmeangivingbacktoGermanythe
48 supremacyinthefinechemicalindustrywhichshepossessedbeforethewar. Theaim
44 45
46 47
Ibid.
218
PostwarProblems,PatriotismandProtection:
219
wastoextendthedurationoftheprovisionsoftheSafeguardingIndustriesAct,whichwas
49 th duetolapseon19 August1924.
TheAssociationofBritishChemicalManufacturersChemist&Druggist101.1(26 July1924):124.
51
SocietyoftheChemicalIndustryChemist&Druggist95.2:(17September1921) 4243.
219
PostwarProblems,PatriotismandProtection:
220
54 atRuncorninCheshire.
IwillnowdescribethesizeofBritishfirmsandespeciallytheirlaboratorystaff,and howfirmsacteddifferentlyandthisbackgroundwillaidanunderstandingofthe interactionswiththeMRCTherapeuticTrialsCommitteeaswillbedescribedinthefinal chapter.ThestrategicdilemmasfacedbyBurroughsWellcomearediscussedingreater detailinthenextchapter,asdirectevidenceisavailablefromtheminutesoftheirScientific andTechnicalCommittee(STC). 5.5.1May&Baker:May&Bakerproducedfinechemicalsandinorganicssuchaslithium beforetheWar.Theirgeneralmanager,WilliamBlenkinsoppssonRichard,waswell suitedtoweighupthepossibilitiesashehadstudiedchemistryattheCity&GuildsCollege inSouthKensington.HisfatherhadbuiltupaninformalrelationshipwithPoulencof Francefrom1909,whichwasformalisedinSeptember1916afterPoulencreceiveda licensetoprepareSalvarsanderivatives.May&BakerboughtafactoryatBellLane, WandsworthandacquiredArthurEwins,theexBurroughsWellcomechemistfromthe MRCaschiefmanufacturingchemist.EwinsappointedGeorgeNewberry,agraduateof theRoyalCollegeofScience,whohelpedduringthewarandjoinedpermanentlyinMarch 1918,andCapt.R.W.E.Stickings,agraduateofKingsCollegewasappointedWorks manager.InSlinnsaccountshefoundthatfewrecordssurvivedtodocumentwartime
53
220
PostwarProblems,PatriotismandProtection:
221
57 EwinstherewereonlythreeotherchemistsatM&Buntil1925. In1924DrT.B.
HenryWellcome,madehugephilanthropicpaymentstowardstheestablishmentofthe
55
57
58
59
221
PostwarProblems,PatriotismandProtection:
222
workonsomeglyoxalines,solubleglycerophosphatesaltsandaseriesofantiseptics.C.E. Coulthard,andJ.MarshallsupportedPymanindevelopingahomologousseriesofphenols,
63 leadingtothedescriptionofnamylmetacresolasanantiseptic. During1927Boots
60
61
J.Slinn,(1984):95110.
ChristopherWeir,JesseBootofNottingham.FounderoftheBootsCompany (Nottingham:TheBootsCompany,1994).
62
F.L.Pyman,C.E.Coulthard,J.Marshall,TheVariationofPhenolCoefficientsin HomologousSeriesofPhenolsJ.Chem.Soc.(1930):280.
222
PostwarProblems,PatriotismandProtection:
223
vanillin.Itwasthroughworkonpatentsforhexylresorcinolandpreparationofalkyl
64 phenolsthatamylmetacresolwasdiscovered,extendingBootsmaininterestinantiseptics.
5.5.4Glaxo: IntheearlypostwarperiodonlyAllenandHanburysandGlaxowereadded
66 tothosewhobegantoproducedrugs. ThecompanylaterknownasGlaxostartedas
Nathans.TheyhadoriginatedfromaNewZealandfirmthathadimporteddairyproduce andtooktheirnewnamefromtheirmilksubstituteadvertisedas:Glaxobuildsbonnie
67 babies. Nathans(Glaxo)grewinnichemarketsthroughdramaticallyincreasedexport
salesofnutritionalproducts,anddriedmilksubstitutesandhadalargerangeofmalted
68 productsduetoconcernsovertuberculosisinfectednaturalmilk. However,they
64 65
S.A.B.Kipping,ChemistryandIndustry (25February1963):3034.
R.P.T.DavenportHinesandJudySlinn,Glaxo:AHistoryto1962(Cambridge: CambridgeUniversityPress,1992):68134G.Tweedale,(1990).
67 68 69
70
223
PostwarProblems,PatriotismandProtection:
224
investigatethevitamincontentoftheirmilkproductsundervariousconditions.Davenport HinesandSlinngaveadetailedaccountoftheearlyworkonvitaminsintheirGlaxo
72 history. DiseasesduetodietdeficiencieswererecognisedbyBlandSuttonin1889and
CasimirFunkoftheListerInstitutecoinedthetermvitamin(e)in1912.Ricketswas
73 knowntobeduetoafatfreedietandcodliveroilwasbeneficial.
R.P.T.DavenportHines,JSlinn,(1992):6897.
224
PostwarProblems,PatriotismandProtection:
225
BacharachbroughtmuchtoGlaxoincludingstatisticalanalysisofbiologicalresults andcolorimetricassaysutilisingnewultravioletspectrophotometers,andby1929Harry
76 JephcottwasaDirector. Glaxosalessufferedinthepostwardepressionandtheirprofits 77 reachedtheirlowestpointin1932beforerecoveringagain.
5.5.5Allen&Hanburys: GeoffreyTweedalecontributedahistoryofAllen&Hanburys
78 fromwhichIcansummarisetheinterwardevelopments. ReginaldHanbury,likehis
grandfatherCorneliusqualifiedasasurgeonandledthesurgicalinstrumentsdivision.The firmhadgrownsignificantlyfromastaffof20in1850to500in1915.Turnoverdoubled duringthewartoreach1m,althoughtheywereleftwithadamagedfactoryatBethnal Green.Theyreliedheavilyonthemilkandmaltedfoodbusiness,butthisplacedthemina positiontotakeadvantageofthediscoveryofvitamins,whichwereaddedtotheirexisting products.Muchoftheirotherproductsarosefromprocessingrawmaterialsintofine chemicals.Allen&Hanburyswereasmallfamilyrunfirmatthestartofthewar,having justhadthesetbackofthedeathsofCorneliusHanburyin1916andtheirchemistWilliam RalphDodddiedin1917. DespitetheirlonghistoryAllen&Hanbury'sturnoveronly reached1millionin1920withover50%duetoitsmilkandfoodproducts,despitea tenfoldrisesince1913.Theyfailedtopayadividendin1919forthefirsttimeandprofits of93,129hadtobesetagainstthelossoftheirRussianfactoryasaconsequenceofthe
79 revolution,andtheirBethnalGreensite,damagedbybombshadtoberebuilt. Theyhad
75
79
225
PostwarProblems,PatriotismandProtection:
226
theirownexpertsciencegraduateinchemicalanalysis,NormanEvers,whojoinedthefirm in1912,havingbeenapublicanalystinBirmingham.HehadtrainedattheInstituteof
80 ChemistryandreceivedhisdegreefromKingsCollege,London. In1922theDangerous
DrugsActnecessitatedtheemploymentoftrainedandqualifiedmenandincreasedtheuse ofanalyticalmethods.Separateanalytical,research,bacteriologicalandexperimental manufacturingdivisionswereestablishedatAllen&HanburysalongtheBurroughs Wellcomelinestocheckthepurityofpurchasedmaterials.Theyalsoestablishedresearch, bacteriologicalandexperimentalmanufacturingdivisions.Thelaboratoriesoccupied120by 40feetofthetopflooroftheBethnalGreenbuilding. TheDirectorofthelaboratorieswas NormanEvers,supportedby7chemistsandanumberofassistants. Accordingto Tweedalesaccount: intheresearchandexperimentalresearchlaboratoriesworkiscarriedout withaneyetothefuture:newpreparationsaremadeinsmallbatcheswith theobjectofdiscoveringhowbesttheycanbemanufacturedonalargescale: oldmethodsofmanufactureareexaminedinthelightofrecentknowledge: investigationsaremadeupon vexedandtroublesomeproblemsinchemistry, 81 pharmacyandpharmacology,andnewmanufacturingplantistested. Asdescribedpreviously,Allen&HanburysplayedasignificantroleintheBritish manufactureofinsulinandestablishedalargemanufacturingunitatGrahamStreet,under thedirectionofFrancisCarrofBritishDrugHouses,theircollaborativepartner,andinsulin contributedsignificantlytoprofits.Glaxogrewasamajorcompetitorinthemilkbusiness andespeciallyafteraddingvitaminstoitsproductsfrom1924,atechniqueinwhichA&H followedfrom1928.A&Hwerebeingmarginalisedintheirpreviouslystrongestareaand thereforesoughtnewchannels,buthadtodowithdecliningincome.
5.5.6BritishDrugHouses: BeforethewarBritishDrugHousesofferedpurifieddrugsin
82 differentforms. Theirchairman,CharlesA.Hill,hadbeenacontemporaryofFrancis
80
G.Tweedale,(1990):127. Chemists&Druggist85.1(29August1914),nearp.51adverts.
82
226
PostwarProblems,PatriotismandProtection:
227
CarratthePharmaceuticalSocietyandacampaignerforpureandstandardiseddrugs.At theendoftheWarheturnedtohisfriendforadviceonhowBritishDrugHousescould
83 enterthesyntheticdrugarea.CarrfirstvisitedBDHinNovember1919. Hesubmitteda
detailedmemorandumofrecommendationsfortheplannedreorganisationofthefirm's researchincludingstaffingdetails,amountsofdrugstobemadeandintermediatesand
84 equipmenttobepurchased.
Theymovedforwardambitiously.FrancisCarrwasaskedtogiveanopinionof whatwouldberequiredtosetupamodernplantforBDH.InamemowrittentoHillin November1919,Carrpromisedthat:withfirstclassequipment,giventimeanychemical canbeproduced.Heestimatedthat: Areasonabletargetforachemistworkingwithtwoboyswouldbetomake15 chemicalpreparationsinayearonascaleof20kg.Withfoursuchchemists andassistantsthe60preparationswouldprobablybeaccompaniedby40 intermediatesandotherscouldbepurchasedfromdyestuffsfirms.Capitalof around8,000wouldbetiedupinstocksandthat3,200wouldbesetaside forpurchasesofintermediates.Thewagesfortheboyswouldbe2perweek togetherwiththechemistssalarybillof1,432.Inordertoattractasuitable technicaldirectorwouldrequireafurther500p.a.Afurther2,500would beneededforthepurchaseof materialssuchasreactionvessels,autoclaves, 85 mechanicalstirrers,vatsandfilters.
boldinhisownsuggestedsalary:
83
F.H.CarrtoC.AHill,(19November1919),B.CARRatImperialInstitute personalnotesofFrancisHowardCarr.
85
F.H.CarrtoC.A.Hill,(23November1919):B.CARRatImperialInstitute personalnotesofFrancisHowardCarr.
86
227
PostwarProblems,PatriotismandProtection:
228
87
F.H.CarrArchive2130B/CARRIVPresscuttings:41.F.CarrtoC.A.Hill,re: ResearchChemists.(23November1923).
88
Chemist&Druggist92.1(14February1920):57.AtthistimeM.R.C.researchers typicallyreceived400500perannum.
89
TheBritishDrugHousesLtd.Chemist&Druggist(20February1926):254Still ProgressingChemist&Druggist(5July1919):46.
90
F.H.Carr,VitaminsPharmaceuticalJournal (18December1926):72934.
228
PostwarProblems,PatriotismandProtection:
229
5.6ProtectingtheBritishPublic:TheMRCandNationalInstituteofMedical ResearchBiologicalStandardisationandGovernmentLegislationofDrugs. WehaveseenhowtheGovernmenttriedtoofferassistancetoBritish pharmaceuticalfirmsintheformofcapitalgrantsduringthewarandtariff protectionpost war.TheGovernmentalsoexpressedconcernsaboutthegrowingsalesofpatentmedicines toagulliblepublic,andthebiologicals,trustedbydoctorsasbeingofreliablestrengthsand yetcapableofcausingseriousharm.IhavedescribedpreviouslyhowtheBMAbroughtthe patentmedicineissuetoaheadwiththeirpublicationsSecretRemediesandMoreSecret Remedies.ThelatestBritishPharmacopoeiahadbeenpublishedaftertheoutbreakofthe war,andithadnotbeenpossibletofocusontheseissuesuntiltheendofhostilities.The wartimelegislationoftheVenerealDiseasesActbeganthisprocessandwasaimedatthe mostflagrantbreaches,suchasquackclaimstotreatsyphilis.AcommitteefortheControl ofPatentMedicineswasalsoannouncedfollowingtotherecommendationsoftheSelect Committeeonpatentmedicinesof1914tofocusonlegislationonthecompositionof patentmedicines,theiradvertisingofclaimsandwhethertheycontravenedthePoisonsAct. ThestancetakenfittedinwellwiththestringenteffortstoprovethatBritishmade
91 Salvarsanwasavalidtherapy.
governmentalsoenactedtheDangerousDrugsActin1920tospecificallycontrolthesale
93 ofnarcoticssuchasopiumandheroin. Addisonsoughttocontinueprotectionof
91
MinistryofHealthEnquiry.SelectCommittee1914Chemist&Druggist92.3(1 May1920):83.
92
229
PostwarProblems,PatriotismandProtection:
230
abrogatedforeignpatentsundertheDefenceoftheRealmActinordertomaintaindrug
94 synthesisbyBritishfirms.
ViscountAstorexplainedduringthesecondreadingoftheproposedProprietary MedicinesBillin1920thattherehadbeencompromises,butallweweretryingtodowas
95 protectthelifeandhealthofthepeople. Theissuesweretheunreliablecontentofsome
drugs,thefactthatselfprescribingledtodelaysinseekingmedicalconsultation,andthat somemedicationswereadvertisedascuringallmannerofdiseases,someofwhichwere consideredincurableinshort,dealingwiththeissueofreliabilityofclaimsmadeby manufacturers. OnewayofprotectingtheBritishpublicwouldbetoexcludeforeigndrugs.The SocietyoftheChemicalIndustry,appealedtothemedicalprofessiontouseBritish rather thanforeigndrugs: Wedonotadvertisetothepublic,nor'prescribe',norinanywaytrespasson therightfulprovinceofthemedicalpractitioneronthecontrary,werelyonthe positionthatthechemist,sofarasthemedicaluseofchemicalsisconcerned,is thehandmaidofthemedicalman,andwemightadd,ratherbluntly,wedonot recommendforeignmedicalmenandhealthresorts.Whyshouldthemedical manrecommendforeignpharmaceuticalpreparations?Thescientificstaffsin ourlaboratorieswelcomesuggestionsfrommedicalmen,andwillcarryout investigationstoelucidateproblemsconnectedwithchemistry,materiamedica 96 andthelike,whichmayproveofassistanceintheartofhealing.
94
96
230
PostwarProblems,PatriotismandProtection:
231
TheChemicalSociety,TheSocietyoftheChemicalIndustry,andtheInstituteof ChemistrywithperhapsthenewlyfoundedABCMto.setupawatchfuland alertjointcouncil,withdirectionstoconsidernationalquestionsinwhichanyof the variousinterestsofchemistryareconcerned,andtomakesuchrepresentationsto 99 ouradministratorsaswouldvoicethecorporateviewofthewholebody. FollowingthiscombinedlobbyingtheKeyIndustriesBill waspassedandcameinto operationon 1October1921.Itimposedadutyonimportsofallsyntheticorganicagents, andaroundseventhousanddefinedfinechemicalsaswellasdyestuffs,opticalglass, wirelessparts,laboratorywares,tungstenandfermentedchemicalsforafiveyearterm.It was: Anacttoimposedutiesofcustomsoncertaingoodswithaviewtothe safeguardingcertainspecialindustriesandthesafeguardingofemploymentin industriesintheUKagainsttheeffectsofdepreciationofforeigncurrencies, 100 andthedisposalofimportedgoodsatpricesbelowthecostofproduction. TheimpositionoftariffsinBritainpolarisedtheBritishpharmaceuticalindustry.The BritishChemicalTradeAssociation,whosememberssoldalltypesofdrugs,wasopposed totheKeyIndustry Billasitdecreasedtheiroveralltrading,manyoftheirproprietary
97
SirWilliamJacksonPope,TheChemistsPartinTherapeuticProgressJ.Soc. Chem.Ind.(15September1922).
100
231
PostwarProblems,PatriotismandProtection:
232
havetohandlethecontroversyaroundthebillinofficeattheBoardofTrade,pointedout thattheexperienceofwaryearsshowedthegreatdangerofdependenceuponforeign
102 sources. Theethicalpharmaceuticalcompaniesacclaimedthetariffs,whichprotected
theirproductionofhighvalueproducts.Asadirectresult,inNovember1921,EvansSons, Lescher&Webbcompletelyrelinquishedtheirtradeinproprietarymedicinesinfavourof
103 ethicalmedicines.
However,protectionintheformoftariffswasnotenoughtoshieldtheBritish pharmaceuticalindustryasitstruggledthroughtheeconomicrecessionofthe1920'sand
104 founditincreasinglydifficulttoexportdrugs. EvenafterthepassingoftheKey
IndustriesscheduleoftheSafeguardingofIndustriesActin1921,itwasclearthatmany hospitalswerestillusingcontinentalremediesand:thatowingtothedutynowimposed
105 wouldhavetopaymore. Thereasonsrangedfromignorancethattheproductswere
101 102
SafeguardingofIndustryActChemist&Druggist95.2(24September1921):57.
Dr.Murray,questiontotheBoardofTrade,MedicinalChemicalsChemist& Druggist95.2(12November1921):6263.
103 104
TheRelinquishmentChemist&Druggist95.2(5November1921):57.
OverseastradebegantoimprovebetweenJulyandSeptember1921,Chemist& Druggist95.1(15June1921):51.
105
Dr.MurrayMedicinalChemicalsChemist&Druggist95.2(12November1921): 6263.
106
232
PostwarProblems,PatriotismandProtection:
233
originalMedicalResearchCommitteeandNationalInsurancefundingceasedon31March 1920,offeringgreaterindependence,andreestablishmentastheMedicalResearch
108 Council.(IcontinuetousetheabbreviationMRCforconvenience) Havingbeen
107
MedicalResearchCouncilBritishMedicalJournal (27March1920):447.The newCommitteeincludedViscountGoschenC.B.E.,MrWilliamGraham,MPfor EdinburghCentral,Hon.E.F.L.WoodMPofRipon,C.J.Bond,F.R.C.S.,Consultant Surgeon,LeicesterRoyalInfirmaryWilliamBullochMD,FRS,ProfessorofBacteriology atLondonHospital,T.J.Elliott,FRSPhysicianatUCH,HenryHeadMD,FRS,formerly physiciantotheLondonhospital,F.GowlandHopkinsFRS,Prof.ofBiochemistry, UniversityofCambridge,MajorGeneralSirW.B.Leischman,MB,FRS,Directorof PathologyintheArmyandDrNoelPaton,MD,FRS,Prof.ofPhysiology,Universityof Glasgow.BritishMedicalJournal (10April1920):51011.
109
W.S.Feldberg,HenryHallettDale(1970):116.
111
BiologicalStandardsandtheTherapeuticSubstancesBillBritishMedicalJournal Suppl.(12September1925).
233
PostwarProblems,PatriotismandProtection:
234
BritainbehindGermanyandAmericaastheonlygreatnationwithnosuchsystem.Dale addressedthisduringthewarwithhisworkonthestandardisationofSalvarsan,and recruitedformercolleaguesfromBurroughsWellcome,includingGeorgeBargerand ArthurJ.Ewins.However,EwinswaspoachedbytheManagingDirectorofMay&Baker in1917andBargeracceptedaChairatEdinburghUniversitytowardstheendoftheWar, leavingDalewithlimitedsupportandrelyingontrustingthefirmstodotheirown testing. Thiswasnotasoundbasisforthescrutinyofdrugs,especiallythoseofforeignorigin. EwinsreplacementwasalsosecuredfromBurroughsWellcomeon30May1919Harold King,anorganicchemistfromtheWCRLrejoinedDaleattheMRCandhispermanent
113 appointmentattheNIMRwasconfirmedinMarch1922.
112
MRCMinutesII,(16December1921):181.
113
HaroldKinghadstudiedchemistryunderK.J.P.OrtonatUniversityCollege, Bangor,graduatingwithfirstclasshonours.HejoinedtheWPRLin1911andalsoworked intheExperimentallaboratoryattheWorks,andduringtheWarhemanufacturedsalicylic acid.StaffRecords,WF:Box25Kingwasappointedatasalaryof800,increasingto 900.MRCMinutesII,(24March1922):266andMRCMinutesII,(27November1923): 161SirCharlesHarrington,HaroldKing18811957BiographicalMemoirsofFellows oftheRoyalSociety 2(1937):157171.HaroldKing,ObituaryTheTimes(18February 1957)HewastheonlyfulltimerattheNIMRuntilaseparatedepartmentwasestablished in1927NIMRearlyhistory,1968,DaleArchives93HD.143.11.
114
MRCReport191920BritishMedicalJournal (10April1920):510511.
234
PostwarProblems,PatriotismandProtection:
235
April1920Addisonappointedacommitteetoconsidernewlegislationandadministrative
115 measurestodealwithstandardsfor:
DaleestablishedaCommitteeonBiologicalStandardsandAssaytocoordinate
117 researchondeterminationandmaintenanceofbiologicalstandards, whichincluded
115
MRCMinutesII,(7July1920):82,101. MRCMinutesII,(15October1920):138(10December1920):192.
BurnwasappointedtothestafffromJuly1921ataninitialsalaryof500p.a. MRCCouncilMinutesII,(18March1921):105.
120
MRCCouncilMinutesII,(20March1920):72.
235
PostwarProblems,PatriotismandProtection:
236
performedagainststandardsbyBurnshowedveryvariablestrengthsofthedifferent manufacturersbrandsofpituitaryextractandsometimesthisvariabilityledtouterine
124 rupture. Thecommitteeagreedthatitwasimportanttohavetherightstrengthof
preparation:aremedyofgreatvaluewhenaccuratelyused,maywheninaccurately
121 122
A.S.Milton,BurnOxfordforaStartBrit.J.Pharmacology 119(1996):12939.
MRCMinutesII,(27May1921):78W.S.Feldberg,HenryHallettDale(1970):
120.
124
236
PostwarProblems,PatriotismandProtection:
237
theMRCshowedthatbiologicalextractssuchasstrophanthin,thecardiacglycoside
126 extractedfromtheseedsof Strophanthusgratus,byThomasFraserinEdinburgh, (and
125
TheLateT.R.FraserChemist&Druggist92.1(17January1920):65.
127
StandardisationofSerumsetc.BritishMedicalJournal (12March1921):399.
237
PostwarProblems,PatriotismandProtection:
238
InternationalstandardswereagreedbetweenFrance,theUSA,GermanyandBritainfor
131 diphtheriaandtetanusantitoxinsataconferenceinParisin1922.
andantipneumococcalteam,wassecondedtoworkandlectureatSirAlmrothWrights
134 unitatSt.Marysfortwoyearstolearnmoreaboutvaccines.
Followingtherevelationsofseveralantitoxinsandseraofvariablestrengthand especiallytheimplicationthattheseweremostlyofforeignorigin,theTherapeutic SubstancesActsweredraftedtomakeitobligatoryforsamplestobetested.Itwasalso recognisedthattheultimatewayinwhichtostandardiseabiologicalextractwasasstated intheMRCReportof1922: Theabsenceofofficialstandardsofvalueandauthenticityfordrugsofthis kindandfornumerousbiologicalpreparations,suchasserumsandthelikeused ingeneralpracticehasbeenpubliclydenouncedasdiscreditabletoournational positionintheworldofscienceandasourceofgravedangertothe community.Itwouldbeagreatadvantageifastablechemicalsubstancecould bepreparedofknownchemicalcompositionwhichactedontheuterusinthe 135 samewayasthepituitaryextract.
131
MRCMinutesII,(20January1922):189.
238
PostwarProblems,PatriotismandProtection:
239
MeanwhiletheTherapeuticSubstancesActtargetedtowardsforeigndrugswasstillbeing guidedthroughparliament.AstatementfromdiscussionsintheHouseofLordsinAugust 1923emphasisedthat: Itisessentialthatdoctorswhenwritingprescriptionsshouldbesurethatthe patientwillhavewhatheintendshimtohavewiththeaimtoensurethatthe standardofgoodscominginshouldbeashighasthearticleswhichwe 136 ourselvesmanufactureinthiscountry. InfactsomegroupssuchastheNorthBritishBranchofthePharmaceuticalSocietysaw noreasontothinkthatthepresentmethodsbywhichthesesubstancesareproducedand placedatthedisposalofthemedicalprofessionandpharmacistsgaveanyoccasiontofear
137 thatadequateprecautionswerenottakentoprotectthepublicintent. Yetby1924the
MRCwasoverrunwithassaystoperformandfrom17July1924theInsurance Commissionagreedtoallowatrialperiodofaround2months,duringwhichBritish manufacturerswereallowedtoperformtheirowntestsontheinsulin,whichtheywerethen producing,withcontrolbatchesbeingsenttotheNIMR.AsmallamountofUSinsulinwas importedbuttheUStestsweretrusted. ArowoccurredbetweentheMRCandtheCanadiansoverthestandardunitsof insulinafterthelattergroupchangedthem.Dalechairedaheateddebateatameetingin Edinburghin1923aboutwhethertouseratormouseunits,andeventuallytheMRC definitionwasupheld. ThemuchdebatedTherapeuticSubstancesBillwasfurtherdelayedin1924bythe attentionfocusedupontheeconomy.TheBillrecommendedthatsubstancesthatcouldnot betestedchemicallyshouldbesupervisedunderacommitteeofthePrivyCouncilassisted byanadvisorycommittee:ItisrecognisedthattheMRCwhichalreadypossessesthe requisiteorganisation,shouldberesponsibleforthiscentrallaboratory. EthicalmanufacturerssoughttocollaboratewiththeMRCtodefinestandardsfor biologicals,tofurtherdistinguishtheirethicaldrugsfrompatentandproprietarymedicines andtobeabletoexportdrugstoAmericaandEurope,wheretightlawsonbiological
136 137
TherapeuticSubstancesBillChemist&Druggist99.1(4August1923):198. TherapeuticSubstancesChemist&Druggist100.2(19April1924):568.
239
PostwarProblems,PatriotismandProtection:
240
regulatorandprotectortopreventthesaleinBritainofproducts,whichhadalreadyfailed
139 testsinothercountries,includingGermany. Theywereparticularlyconcernedaboutthe 140 toxicityofthearsenobenzols.
In ordertorelievethealreadyoverworkedlaboratoriesoftheNIMRitwas proposedattheendof1924thatthePharmaceuticalSocietywouldestablishalaboratoryif
141 theTherapeuticSubstancesActbecamelaw. DaleandFletchersupportedthe
138
InMarch1924HarrisonvisitedthePasteurInstitutetodiscussanobserveddecrease oftheefficacyofStovarsolMRCSalvarsanFileMB22,(6March1924):89
141
TherapeuticSubstancesRegulations,DaleArchives93HD21.2.126)1925.
240
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241
JoshuaBurnwasappointedDirectoroftheLaboratoryatthePharmaceutical
146 Societyon24October1925,whichbecameoperationalatthestartof1926. Rather
thanjustperformroutinetests,heexploredthereasonsfortheirvariationandrecognised thatdifferenceswerenotonlyduetovariationinthemechanismofextraction,butalsoan inherentbiologicalvariabilityofactionandresponse. Burnwrote: Thesurprisingfactwasestablishedthatthedoseperbodyweightrequiredto produceoestrusin50%ofovariectomisedmicewasthesameasforrats,when resultswereexpressedasameaneffectinagroupofanimalsandarevolution ofthinkingwasrequiredbeforeitwasrealisedthatallresponsesmustbetaken intoaccountincludingtheoddonesandthatthecorrectresponsewasthemean 147 ofallthesevaryingresponses. InDecember1926,thenumericalmethodsappliedtobiologicalstandardisationwere strengthenedfurtherbytheappointmentofJohnHenryGaddum,anotherformer BurroughsWellcomeman,tothebiochemistryandpharmacologysectionoftheNIMR. GaddumhadqualifiedatCambridgeinMathematicsandMedicineandstudiedinthe famousphysiologydepartment,andthenatUCH,London.GaddumthenworkedunderJ.
148 W.TrevanattheWellcomeResearchLaboratoriesfromJanuary1925.
144
MRCMinutesII(16October1925):151MRCMinutesII(29January1926):11(5 March1926):32and(28May1926):94.
145
InternationalCongressofBiologicalStandards,DaleArchives,93HD146.4II.
146
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PostwarProblems,PatriotismandProtection:
242
organs,andthesealsovariedfromdaytodayinthesameanimals,formingthebasisfor
149 alwaysneedingtocomparetheresultsagainstaknownstandard. BoththeMRCandthe
PharmaceuticalSocietyadoptedBurnandTrevan'srevolutionaryconceptsastheyfitted intotheirownschemesofindependenttestingandthedevelopmentofinternationally
150 definedstandards.
Justaheadofthe1927TherapeuticSubstancesAct,NormanEversgavea presentationtotheRoyalSocietyofArtsonChemistryandtheSupplyofDrugsinwhich heemphasizedthegrowinginfluenceofchemicalapproachestodrugdevelopment. Whereasattheendofthenineteenthcenturytherewaslittlestandardisation,afirmnow producing1,000drugsneededtohavechecksinplace: Themedicalprofessionmustbeprotectedandthepublicmustbeprotected againsttheintroductionofnewdrugswithexaggeratedstatementsof efficacy.Theliteratureofsyntheticdrugmanufacturesofthesetimesindeed remindoneofrosecataloguesratherthanscientificproductionsinthe 151 unstintedpraise. Chemistrynowcontributedtotheisolationoftheactiveprinciplesofnaturaldrugs,the elucidationoftheconstitutionofnaturaldrugs,thesynthesisofnaturaldrugs,the modificationofthestructuretochangethephysiologicalaction,preparationofpure suppliesofinorganicdrugs,thepreparationofdrugsinaformsuitableforadministration andanalyticalcontrols.AnewdepartmentwasestablishedatthePharmaceuticalSociety
152 fortestingvitaminsfromAugust1927. Despitetheestablishmentofformalisedtesting,
theTherapeuticSubstancesActcouldonlypreventovertmalpracticeandcarelessness. SubsequentlytherewereminorchangestotheTherapeuticSubstancesActfrom21st
149
Standardisationofremedies,Lancet(10March1928):508.
242
PostwarProblems,PatriotismandProtection:
243
MRCfortestingandnomaterialscouldbesoldafterreachingtheirexpirydate.Resales wereprohibitedinthesamecontainersanddetailsofthepurityandmicrobiologicalcontent
154 hadtobeestablished.
Markedvariationofstrengthsofstrophanthinandpituitaryextractremainedan
155 issuein19289,yetthenumberoffirmsproductsbeingtestedwasstilllimited. The
AnnualReportofthePharmacologicalLaboratoriesofthePharmaceuticalSocietyfor1929 showedthatonly153sampleswereassayed,andthemajorityofthetestsweredoneon
156 fourofthemostdifficultmedicinestostandardisebutalsothemostimportant.
ThepublicationMethodsofBiologicalAssay,byJ.H.Burnin1928begantobe
157 referredtoas'thebible'forbiologicalstandardisation. In1930Burnsummarisedthe
principlesofbiologicalstandardisation:thetestsmustbecomparative,andtheymustbe basedonaquantitativedeterminationoftheanimalvariation...theseprincipleshavebeen
153
TherapeuticSubstancesRegulations(21February1927)(31May1927)Dale Archives93HDBox21.2126147(192562).
154
243
PostwarProblems,PatriotismandProtection:
244
showntobecapableoftransformingthewholesubjectfromtheplaneofaninsidious
158 meansofselfdisciplinetothatofawellorderedandprogressivescience.
Duetothepracticalimpossibilityofmaintainingoverseasstandardsforeach
159 medicine,insteadtheimporterwaslicensed,andin1930sixlicenseswerecancelled.
Theworkonbiologicalstandardisationreflectedacontinuityofoperationincluding
161 Dale,Brown,Burn,Gaddum,TrevanandUnderhill. EventuallythePharmaceutical
Inconclusion,inthedecadeaftertheWar,firsttheMRCandthenalsothe PharmaceuticalSocietyestablishedlaboratoriesfortheroutinetestingofbiological
158
J.H.Burn,TheErrorsofBiologicalAssayPhysiologicalReviews10(1930): 14661.
159
Therewerespecificguidelinesforvaccinesofantityphoid,antiTAB(typhoidand paratyphoid),TABC(typhoid,paratyphoidandcholera),plague,dysentery,whooping cough,tuberculosis,theSchicktest(toxinandcontrol),diphtheriaprophylactic,tuberculin, tuberclevaccine,diphtheriaantitoxin,andtetanus,arsenobenzenes,novarsenobenzeneand Sulpharsan.StateControlofTherapeuticSubstancesBritishMedicalJournal (27June 1931):588TheMRCtestedover300kindsofcatgut,vaccinelymph,antiserafortoxinof B.welchii,antidysentaryserum,strophanthustincturesandeverybatchofarsenobenzines: MRCReportSeries192930(London:HMSO,1930) BritishMedicalJournal (14March 1931):4468:DaleArchives,93HD21.2.1289.
161 162
244
PostwarProblems,PatriotismandProtection:
245
163
AlbertMondwasthechairmanofBrunnerMondfrom18941916,retiringin1923.J. Chem.Soc.(1931)II:332439W.J.Reader,(1970):4823.
164
D.S.LCardwell,TheOrganisationofScienceinEngland(London:Heinemann,2nd edition1972).
165
L.F.Haber,(1971):359.
245
PostwarProblems,PatriotismandProtection:
246
whoactedasaconsultanttoBurroughsWellcome,hadusedthetermchemicalengineer
166 inBritainasearlyas1906butsuchchemistswererarities.
awardedaC.B.E.forhiswartimedrugproductions.In1921hecapturedthisexperience bypublishinganimportanttextonorganicmedicinalchemicals,whichdetailedmethodsof
168 productionofmanynewdrugs. Carrdevelopedaspecialinterestinthetrainingof
firmswasinsufficientforagrowingindustry,requiringprocesscontrol,researchand
170 analysis. Carrplayedanactiveroleonthecommitteesofvariouschemicalsocietiesand
usedthisplatformtocampaignforbettertrainingofchemistsandforchemicalengineering
166
ReportoftheUGC,(London:HMSO,1921),Cmd1163:12:M.Sanderson,The UniversitiesandBritishIndustry18501970(London:Routledge&KeganPaul,1972).
246
PostwarProblems,PatriotismandProtection:
247
tobeaffordedacademicstatus.171 Thefirstchairinchemicalengineeringwasassignedin
172 1923atUniversityCollegeLondon.
ThelargestlaboratoryinBritainwasthatoftheBritishDyestuffsCorporation (BDC),whichhadaresearchstaffofaround150byJanuary1923,butthisstillcompared
173 withover1,000inthelargestGermanconglomerate. Britishdyefirmshadnottakenup
thechallengetoinvestforthefuture.BDC'sresearchstaffactuallyfellfrom50to30over
174 theperiod19201923andwas19in1924.
Carrwaspartofagroupadvocatingtheunionofchemistrywithchemical engineeringasanacademicdiscipline.Carrfeltthatathreeyearacademiccoursedidnot adequatelyqualifyachemistforpracticeandthatafurtherpostgraduateyearwas required.Trainedchemistsneededtoknowhowtoreactifchemicalreactionsproceeded alongunexpectedlines.Theyneededtoincreaseyields,andreducelabourcosts,suggest appropriatematerials,understandthermodynamics,chemicalkinetics,fueleconomy, constructionofplant,andengineering.Theserequirementswereespeciallyacuteinthe pharmaceuticalindustry,wherecontinuousproductionprocessescouldnotbeused,sofine chemicalstendedtobebatchprocessed.Quitesmallchangesofconditionscouldresultin largechangesofyields,andhencecosts.Inaddition,themodernmanufacturingchemist neededtolearnsomeaspectsofmanagement,costingandaccountancy.Carrhadastrong platformforhiscaseashisfamespreadinternationallyfollowinghislargescaleproduction
175 ofinsulin,makingBritainselfsufficientin1923(discussedinchapter6).
171
M.R.Fox,(1967). L.F.Haber,(1971):355.
247
PostwarProblems,PatriotismandProtection:
248
IvanLevinsteinrecognisedsimilarrequirementsfordyestuffschemists,sayingit
176 required5yearstrainingplus2yearsacquaintanceinordertobefullyfunctional. He
requiredcompetentworksmanagerswithknowledgeofscience,engineering,and quantitativethinkingonquestionsofenergyandhewasloathtotakeonforeignchemists
177 insteadofourown. However,Britishuniversitychemistscontributedmostlyto 178 theoreticalratherthanthemoreurgentlyneededpracticalknowledge.
Carr,alreadyanexamineratLondonUniversity,foughtlongandhardagainstthe closureofFinsburyTechnicalCollegeunderSirWilliamJ.Pope,afteritwasannouncedin
179 May1924thatitwouldcloseinJuly1926. InOctober1926CarrwaselectedPresident
176
57.
177 178
179
TheFinancialNews(17June1926)inCarrArchivesF.H.CarrlettertoTheTimes (5December1925).
180
2130B/CARRhandwrittennotesofFrancisHowardCarr,ImperialCollege,1926
248
PostwarProblems,PatriotismandProtection:
249
coloniesthathadprovidedmedicinalplants,leadingherfirmstofocusevenmoretowards
184 syntheticdrugsashighervalueproductswithlesscompetition. Withfavourable
181
FinalReportoftheCommitteeonIndustryandTrade(London:H.M.S.O.,1928) Cmnd.3282:217218.
182 183 184
E.Moonman,ReluctantPartnerships(London:VictorGollenz,1971):66. W.J.Reader,(1970):317.
SirWilliamPope,TheManufactureofChemicalProducts,Societyofthe ChemicalIndustrymeeting.Chemist&Druggist95.2(17September1921):4243.
185
249
PostwarProblems,PatriotismandProtection:
250
GermanywouldleadtorisesinpricesofcertaindrugssuchasAspirinbyforcingsomeof
187 thesmallerfirmsoutofbusiness. Recollectionsoftheperiodwerearapidrecoveryof 188 theGermanchemicalindustry.
FromtheGermanperspective:DerKriegwarzwaroffiziellbeendet,wurdeaberin
189 andererformweitergefhrt. Overproductionpostwarledtoanexpansionofcartels.
In1905,Germanyhad23chemistryanddyecartelsincluding7inpharmaceuticalsby 1923
190 therewere93cartelsinplace. Inretaliation,theABCMinitiallyofferedarangeof
191 drugsatorbelowcosts,butcouldnotcompeteonpricesinthelongerterm.
186
TheFineChemicalMarketChemist&Druggist99.2(3November1923):621P. Frankland,TheChemicalIndustriesofGermanyinW.M.Gardner,(1915):379388.
188 189
GermanTradeandtheMarkChemist&Druggist95.2(8October1921):5657.
Editorial,TheFineChemicalMarketChemist&Druggist93.2(11December 1920):6465.
192
L.F.Haber,(1971):2745.
250
PostwarProblems,PatriotismandProtection:
251
wereestablishedinWelwynin1908,CIBAinHorshamin1919,SandozinLondonand
195 Bradfordin1921andGeigy,inManchester,butnotuntil1940.
AstheBritishchemicalanddyeindustrycameundergrowingpressurefrom Germany,BDCbegantodiscussmarketshareswithI.G.Farbenasnooneelsecould
196 makedyestuffs,socheaply,soplentifully,norhadthesalesandtechnicalbackup. Had
BDCacceptedtheirterms,thenIGwouldhavedominatedthemanufactureofchemical
197 intermediatesintheUnitedKingdombuttheBritishgovernmentblockedthis.
However,inNovember1923theGovernmentsoldsharesinBDCallowingreorganisation underanewchairman,LordAshfield(SirAlbertStanley)whowasjoinedontheBoardby
198 AlfredMondandDr.E.F.Armstrong.
Towardstheendof1924theLabourGovernmentwasconsideringwithdrawalfrom itsassociationwiththeBritishDyestuffsCorporation,butMcDonald'sGovernmentfellin
199 Octoberbeforeadecisiononmarketshareswasagreed. Labourministerswereopposed
tosuchanagreementbutweredividedonhowtoreorganiseBDCuntillatein1925. BaldwinrecommendedsellingBDCandusingtheproceedsofthesaletodevelop,through
193
JohnF.Marion,TheFineOldHouse,SmithKlineCorporationsFirst150Years, (Philadelphia:Smith,Kline,1980):130.
195
AllanDuckworth,RiseofthePharmaceuticalIndustryChemist&Druggist156 (10November1959):127139.
196 197 198
199
251
PostwarProblems,PatriotismandProtection:
252
theDSIR,facilitiesforpursuingchemicalinvestigationsnotnecessarilytothemakingof drugs,butofvaluetothefightingservicesandtothechemicalindustrygenerallytoensure
200 thatBritainwasselfsufficientinimportantchemicalintermediates.
ThethreattotheBritishindustryincreasedinSeptember1925withthe announcementoftheplannedmergersofthemajorGermansyntheticdyeproducers,who
203 alreadydominatedthesyntheticpharmaceuticalsindustry. Incontrast,theBritish
chemicalanddyestuffsindustriesremainedwidelyfragmented.InhisStreatfieldMemorial lectureof3December1925FrancisCarrdiscussedthe'scientificbasisofindustry'and
204 urgedclosercollaborationinBritain. By1926theGermanmergerswerecompleted
200
PRO,CAB/24/165ReportoftheBDC,26July1924:5CAB/24/175Reportby ChairmanofCommitteeonCivilResearch,(16October1925)P2.
201
th ABCM9 AnnualmeetingChemist&Druggist103.1(25July1925):105the samepatternwasreportedbytheSocietyfortheChemicalindustry,Chemist&Druggist 102.1(6June1925):803. 202 th ABCM,9 AnnualMeetingChemist&Druggist103.1(25July1925):105.
203
By1925Britishexportswereonly84%of1913levelsandimportswere120%,A. J.PTaylor,(1988):238.AchangeinGermanlawin1923encouragedmergers.The originalDreibundofBASF,Bayer,andAGFAamalgamatedwiththeHoechstgroupon18 August1916.In1925theyaddedKalle,Cassella,GriesheimElektronandWeilerterMeer tobecomethefourthlargestfirmintheworldafterGeneralMotors,U.S.Steel,and StandardOil,withaannualturnoverof20mI.G.comprised48%oftheGerman chemicalindustryand66%ofitsprofitsPeterHayes,IGFarbenintheNaziEra:The NascentConcern18601933 (Cambridge:CambridgeUniversityPress,1987)L.F. Haber,(1971):123,andChapter10:27991.
204
252
PostwarProblems,PatriotismandProtection:
253
creatinganextendedInteressengemeinschaft,knownasI.G.Farben,employing7,200and
205 withaturnoverof50mthatthreatenedtoengulfBritishindustry. Themergerallowed
therationalisationofpurchasing,patents,research,andsaleswithcentralofficesin Leverkusen.ThethreepharmaceuticalfirmsMerck,C.F.Boehringer,andKnollalso
206 formedtheirownseparate'Interressengemeinschaft'inGermany.
woundupwithacapitalof100mtoprotecttheirname,andthenextweekwerere
208 establishedasBDHplc. SirAlfredMondcombinedtheBritishchemicalindustries,
BrunnerMond,Nobel,UnitedAlkaliandtheBritishDyesCorporationtoformImperial
th 209 ChemicalIndustries(ICI),announcedpubliclyon26 October1926. Thusanall
embracingnationwidechemicaltrustwascreatedinBritainandcombinedallthemost
210 importantchemicalbranches. SirAlfredMondspoliticalcareerhadendedwiththefall
ofthecoalitiongovernmentin1922helosthisseatin1923andtookoverasChairmanof
211 BrunnerMond.
Anotherwayinwhichcompetitionwaseliminatedafterthemergerswasthrougha
212 seriesoffurtheragreementsonmarketsharebetweenIGFarben,ICIandDuPont.
SimilarmergersoccurredintheUSAwhereDuPontandAlliedChemicalcombinedin
205
M.R.Fox,(1987):16971. L.F.Haber,(1971):289.
206 207
A.J.Levine,IndustrialRetardationinBritain18801974(London:Weidenfeldand Nicholson,1967):53.
208 209
TheBritishDrugHousesLtdChemist&Druggist104.1(20February1926):254
212
253
PostwarProblems,PatriotismandProtection:
254
ArnoldRenshawM.D.oftheLaboratoryofAppliedPhysiologyandPreventative MedicineinManchesterwrotethatthe:recentmergingoftheoutstandingBritishchemical companiesintoasingleorganisationishailedbyscientificmenasoneofthegreateststeps towardstheeconomicprosperityofthechemicalindustry.Hefeltthatthenewcompany ofICIcouldrestore'nationalhonour'andthattherewasnownolongeranobstacleto competingwithGermanrivalssothat: WhilstcongratulatingtheGermaninvestigatorsupontheirachievementin theintroductionofdrugsofthetypeofSalvarsanandBayer205,wemay 215 envythefacilitiesandresourcesuponwhichtheyareabletodraw. BythishemeantthatBritainwouldnolongerbedependentonGermanyforchemical intermediates,andthiswouldbenefitthepharmaceuticalindustry.Therewasstillalotof progresstobemadeinestablishingresearchandmanufacturingcapacityontheGerman lines. 5.9Conclusions. Duringthe1920s,Britishfirmsthathadembarkedondrugsynthesisbeganto producesimpleorganicchemicals.Manyofthenewcompoundswerevariantsonnew agentsappearingelsewhere.TheDangerousSubstancesActof1922mandatedthe employmentoftrainedstafftodealwithpoisonsandotherdangerousdrugsandthisfurther stimulatedthedevelopmentoflaboratories.Processesandmanufacturingcapacitywere improved:anexampleofasmallstepwiseimprovementwasthepreparationofbetaeucaine (Benzamine)ratherthanthenaturallyoccurringalphaeucaine.Thismaynotseeman excitingdevelopmentbutthenewpreparationwasimportantatthetimebecauseitwasfar
213
254
PostwarProblems,PatriotismandProtection:
255
departmentwasexpandedin1929,workonhexylresorcinolledtothesignificantly improvedantiseptic,amylmetacresolandseveralfurtherderivatives,whichweremore
217 solubleandbettertolerated. Severalcompaniesexpandedtheirfacilitiestoproduce
216
217 218
M.Robson,ThePharmaceuticalIndustryinBritainandFrance19191939: (London:PhD,June1989):7.
219
J.V.Pickstone,WaysofKnowing.ANewHistoryofScience,Technologyand Medicine(Manchester:ManchesterUniversityPress,2000):164.
255
PostwarProblems,PatriotismandProtection:
256
producebiologicallystandardisedhormonesandvitamins,inorganicdrugs,andalkaloids andtheirsyntheticeffortswereprimarilythose,whichCarrproposed,ofgradual improvementsofmethodologyforpurifyingtheactiveprinciplesinbetteryields.Whilethis chaptershowedthatingeneralBritishpharmaceuticalfirmsexpandedtheirchemistry efforts,furthersupportisgiveninthechapteronBurroughsWellcomeandtheirScientific andTechnicalCommittee,whichexaminesinmoredetailthedilemmascausedbythe alternativepotentialstrategies. Thedearthofchemistsintherespectivecompaniesupto1927mayexplainthe apparentlackofinnovationsbyBoots,May&Baker,EvansandBurroughsWellcomein thisperiod,althoughanotherstrongreasonwasthesuccessoftheorganotherapiesand hormones,whichofferedanalternativetodirectcompetitionwithGermany.Furthermore, severalofthesecompaniessufferedthelossofkeymembersofstaff. Nevertheless,significantimprovementshademergedintheBritishpharmaceutical industryfrom1922and1926suchthatby1931MiallcoulddescribetheCooperation, whichistakingplacebetweenthechemistandbiologist,thechemistandphysicistand
221 betweenthechemistandengineer.
256
PostwarProblems,PatriotismandProtection:
257
foreigndrugs.MuchoftheinitialexpertiseattheMRCcamefromBurroughsWellcome andtheycontinuedtosecurestafffromBurroughsWellcomesuchthatconcernswere raisedatonestage. However,basedupontheclosecollaborationofBurroughsWellcomewiththe MRC,Britainemergedfromapositionofweaknesstotakeasignificantinternationallead inbiologicalstandardisation.TheTherapeuticSubstancesActconfirmedtheimportant centralroleoftheMRCandlaterthePharmaceuticalSocietyheadedbyJ.H.Burnindrug standardisationandhelpedtoprotectBritainfromimportationofdrugsthathadnotbeen tested.By1928Dale,bynowtheoverallDirectoroftheNIMR,andFletcherwere increasinglyinfluentialindecidingthefateofmedicines,andbothwereinvitedtositonthe
223 PharmacopoeiaCommission. TheMRChadbecomeapowerfulcentralbodyforthe
223
MRCMinutesIII,(22June1928):83.
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258
CHAPTERSIX:TheCampaignforClinicalTrials.
1 Interestingnewcompoundsarediscovered.Interestingnewdrugsaredeveloped.
6.1Introduction. Thisisthesecondchapterofthreecoveringtheperiod19191931.Chapter5dealt withthegeneralproblemsfacedbythepharmaceuticalindustryintheinterwarperiod, Chapter7isacasestudyofBurroughsWellcomestrategyinthisperiod.Thischapter dealswiththespecificproblemofhowBritishfirmscampaignedtogettheirnewdrugs testedclinically. Havingcollaboratedcloselywiththepharmaceuticalindustryduringthe war,particularlyregardingSalvarsan,theMRCbecamethefocusofmedicalresearchin Britain,developingaseriesofclinicalresearchcentreslinkedtopatientcare,and establishedthemselvesasarbitersofdrugquality.AftertheWar,withtheestablishmentof theNIMRatHampsteadin1919,theroleoftheMRCinthestandardisationofnovel medicineswasformalised,toensurethatdrugscouldbeusedreliablywithknownpotency (chapter5).Inadditiontobiologicalstandardisationofdrugs,theMRCclinically evaluatedsomenewdrugs,firstretrospectivelyandthenprospectivelyandshapedthe regulatoryframework.AttheendoftheWartheworkofthesecondSalvarsan CommitteecontinuedasdescribedinChapter4.FromtheirfirstmeetingoftheMedical ResearchCouncilinJuly1920,Fletcherintroducedtheconceptofsmall,specialised coordinatingsubcommittees,whichrecommendedresearchgrantstoindividualsand
2 institutions,andwhichoversawresearchstudies. Theywerealsothemeansbywhich
theMRCconsideredsmallclinicalstudiesofanypromisingnewagents,usuallyarising
3 fromacademia.
W.M.FletchertoSirGeorgeNewman,ChiefMedicalOfficerattheMinistryof Health,(7May1918),MRC1381/1.
3
258
TheCampaignforClinicalTrials
259
throatTabloids,alltheycouldsaywasthat:SirMorrellMacKenzielikestheideaorthat theirmaltextractwassubmittedtomanytherapeutistsandageneralopinionhasbeen
5 expressed. DuringtheWartheMRCtestednotonlySalvarsan,butalsosomeother
conclusionsthattheacademicclinicalresearchbasewasquitelimitedbyreviewingonly
4
259
TheCampaignforClinicalTrials
260
supportgivenandidentifyfurthercentres.SteveSturdystudiedthedevelopmentof
10 clinicalscienceindetail,particularlyEdwardMellanbysdepartmentatSheffield. More 11 recentlyHelenValierexaminedresearchinManchester andMalcolmNicolsonin 12 Glasgow.
andparatyphoidvaccinesandontropicaldiseasesincludingbilharziaandcholera.
8 9
C.C.Booth,ClinicalResearchinJ.Austoker andL.Bryder(eds.),(1989):205241.
ReviewofMRCMinutesIII,(192027).
260
TheCampaignforClinicalTrials
261
ProfessorWarringtonYorkewasresponsibleforresearchattheTropicalResearchUnitin
15 Liverpool.
A.H.CroucherofEastbourne,whoclaimedhehadusedthemethodsince1896gavethe MRCaclearinsightintohowhethoughtitshouldbestudiedinclinicaltrials. Ipersonallywelcomeanyfairandopentrialofanymethodofspecific treatment,whichismostsurelythemethodofthefuture.Butitmustbeareal trialoftherelativemeritsofoursystembycompetentjudgeswhohavemade 17 themselvesauthoritiesbyworkandnotbyofficialposition. Croucherarguedthathehadsetdowntherequirementsforatrialdesignasearlyas1912. Hestatedthattheremedyshouldbetheonlyremedyusedintreatment: Itshouldbeexploitedinaconsecutiveseriesofcasesofallkinds(notmerely especiallyselectedcases)andallthecasesfullytreatedshouldbepublished. Aftertreatmentthecasesshouldbecarefullywatchedandexaminedforat leastthreeorfouryearsbeforeafinaljudgmentisgivenuponthevalueofthe remedy.Theresultsshouldbearrangedinthesegroupsorbetter,asinmy ownrecordsinfivegroups,accordingtothecharacteranddegreeofthe 18 changesinthelungs. InfactthequestionsabouttheSpahlingertreatmentremainedandtheMRCwereaskedby agroupofMPsforastatementonitsmeritsandalthoughtheyreferredthequestiontothe
19 TuberculosisCommittee,intruththeyhadnoconclusivedata. AsIwilldemonstrate
suchelaborateclinicaltrialsremainedonlyatheoreticalconceptforalongtime.British
15
TheCampaignforClinicalTrials
262
firmssimplywantedaquickratificationinsimplestudiesandinsmallgroupsofpatients sothattheycouldselltheirproductsandtheMRCappearedtohavetheinfrastructureto achievethis. AlthoughtheMRCestablishedacentralroleinclinicalresearch,thereweresome opponents.AustokerdiscussedthebattlegroundbetweentheRoyalCollegesandthe emergingspecialitiesintheinterwarperiod.LordsMoynihanandDawson,representing theRoyalCollegesofSurgeonsandPhysiciansrespectively,sawtheMRCasathreatto theircentralcontrolandwereconcernedatseeingadivergencebetweenresearchand medicalandsurgicalpractice.Theyfeltthatphysiciansratherthanscientistsshoulddirect researchandtheysawsomeoftheresearchsponsoredbytheMRCaslackingclinical relevance.However,FletchersviewthatAcommitteeofeminentclinicians...will...be perfectlyuselessaswellashighlyembarrassingindirectingclinicalresearchantagonised
20 hisopponents. LordMoynihanmadeaseriesofcomments:physiologistscouldnot
21 introducenewmedicinesandtheywerealooffrommedicine. Moynihanand
20
21
22
262
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Council didstudytheeffectsofRadium.In1923afurtherfundingbody,theBritish
23 EmpireCancerCampaignwassetup,toworkwithoutconflict.
FletcherinvitedDawsontojointheMRCCommitteein1931,thoughthisdidnot
24 stopfurtheroutbursts. AclinicalcommitteeincludingDawson,Trotter,Edward
25 MellanbyandLewiswasappointedtoadvisetheCouncilregardingclinicalresearch.
DawsonwasinfluentialandhadbeenPresidentoftheRoyalSocietyofMedicineandhe becamePresidentoftheBMAin1932. Fletcherfundedaninternationallyrenownedresearchnetworkofphysicians, physiologists,bacteriologistsandsurgeons,manyarisingfromCambridgeandUniversity CollegeHospital,butalsoothermajorLondonhospitalssuchasSt.Bartholomews,and St. ThomasaswellasSheffield,ManchesterandGlasgow.26 Thenetworkexpandedas investigatorsmovedfromUCHandCambridgetoestablishresearchcentreselsewhere. In1919St.BartholomewswasthefirsttoappointaProfessorofMedicine, ArchibaldGarrod,thoughhemovedtoOxfordtosucceedSirWilliamOsler.Francis RichardFraserwasappointedProf.ofMedicineatStBartholomew'sin1920,wherethe MRCalreadysupportedC.H.AndrewesandE.A.Carmichael,respectively thefuture DirectorsoftheCommonColdUnitinSalisburyandaresearchunitattheNational
27 HospitalinQueensSquare,andMrF.H.K.Green.
23
J.Austoker,WalterMorleyFletcherandtheOriginsofaBasicBiomedical ResearchPolicyinJ.AustokerandL.Bryder(eds.),(1989):2333.
25 26
MRCMinutesIII,(21October1932):160.
263
TheCampaignforClinicalTrials
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ThomasLewiswasfundedbytheMRCandbecamethefirstfulltimechairand DirectorofClinicalResearchattheDepartmentofClinicalResearchandExperimental
28 TherapeuticsatUCHin1920. Col.T.R.Elliott,itsnewProfessorofMedicine 29 collaboratedwithDaleduringhistimeatBurroughsWellcomeandtheMRC. Dale
wroteT.R.Elliott,ThomasLewisandWilfredTrotterweregiantsofUCHwherethe firsttentativeessayswerebeingmadeintheapplicationofscientificmethodstoclinical
30 problems. Elliottdemonstratedthatanacademicunit,combiningteaching,research 31 andcareofpatients,couldactuallybemadetowork. ArthurRobertson Cushnywas
ProfessorofPharmacologyatUCH,andlatercontinuedhisstructureactivitystudiesin
32 Edinburgh.
28
Lewissalaryroseto2,000MRCMinutes,(30January,1925):11Hestudied atropineforatrialfibrillationandquinidine,MRCReport110(1922)W.R.Merrington, UCHanditsMedicalSchool:aHistory (London:Heinemann,1976):118,192 MRC Report19201 (London:HMSO,1922):2328ArthurHolman,SirThomasLewis, PioneerCardiologistandClinicalScientist(Godalming:SpringerVerlag,1986)C.C. BoothinJ.Austoker andL.Bryder(eds.),(1989):208210.
29
32
A.LandsboroughThompson,(1975):27.
264
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34 Prof.J.C.Meakins. EdinburghwasalsothenewhomeoftheformerBurroughs
Twofurtherresearchers,whohadcollaboratedwithLewis,movedtoCambridge.
40 Thepathologist, AlanN.Drury, hadbeensupportedatUniversityCollegeandhis
34
MRCMinutesII,(24March1922):250(4May1923):63.
35
FletchermetFlexner,Roux,Calmette,Bernard,BordetandMadsenandtraveledto theU.S.A.onseveraloccasions,visitingMcGillUniversity:MaisieFletcher,(1957).
36
W.R.Merrington,(1976):123AbrahamFlexner,MedicalEducationintheUnited StatesandCanada(NewYork:CarnegieFoundation,1910):116.
38
MRCMinutesII,(20July1923):91(17July1925)D.CantorinJ.AustokerandL. Bryder(eds.),(1989):199.
39
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41 fundingcontinuedattheDepartmentofPathologyattheUniversity ofCambridge. R.
T.GrantwasappointedtotheDepartmentofExperimentalMedicineon11May1928,but heleftforCambridgeinOctober1928(andsubsequentlyheadedthenewclinicalresearch
42 unitatGuysHospital,thefirsttoemergedirectlyfromLewisdepartment. In 43 44 Manchester,E.J.Wayne workedonthemetabolismofinsulin. GeorgeW.Pickering
Leeds)andJohnBeresfordLeathes(exSheffield,exToronto)asProfessorsof
47 PhysiologyinManchester,afterHillwenttoUCH.
Thesewerethemenwhoweretobecentralintheclinicaltestingofnewdrugs. TheMRCresearchattheCentralResearchInstitute,MountVernon,Hampsteadwas
41 42
MRCMinutesIII,(24June1927):106.
MRCMinutesII,(22October1926):181.
45
PapersbyL.BryderandJ.AustokerinJ.AustokerandL.Bryder(eds.),(1989):10, 46,53,63.
46
MarkWeatherall,Gentlemen,ScientistsandDoctors:MedicineatCambridge1800 1940.(Cambridge:BoydellPress,2000).
47
MRCMinutesII,(1January1920):42.
266
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50 theNIMRwereunderHenryDalewhowasappointedDirectoron1June1928.
TheMRCestablishedsubcommitteesforthestudyofrickets,(includingHopkins,
51 Paton,andEdwardMellanby) ,ahaemoglobincommittee(JoshuaH.Burn,52 D.Murray 53 LyonofEdinburghInfirmary), ananaestheticscommittee(includingProf.H.B.Dixon
48 49
50
51 52 53
MRCMinutesII,(29January1926):8.
267
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56 FrederickGowlandHopkins, chairedanAccessoryFoodFactorsCommittee,
establishedjointlywiththeListerInstitutein1918,includingHarrietteChick,Jack
57 58 DrummondatUniversityCollegeHospital , thebiochemistArthurHarden andEdward
Mellanby(whowemetpreviouslyinatemporarylaboratoryroleatBurroughsWellcome
59 withhisbrotherJohn). From1923EdwardMellanby wasProfessorofPharmacologyat 60 Sheffield,andthenUCH. TheMRCalsosupportedfurthernutritionalresearchbyNoel
61 Paton,RegiusProfessorofPhysiologyattheUniversityofGlasgow. Amoregeneral
62 63 Nutritioncommittee wassetupin1929withProf.EdwardProvan Cathcart
(chairman),JohnBoydOrr,andcontinuedsupportfromHopkins,DrummondandChick. TheMRCstatistician,MajorGreenwood,ProfessorofEpidemiologyandVitalStatistics
56
H.Kamminga,F.G.HopkinsandtheUnificationofBiochemistryTrendsIn BiologicalSciences (22May1997):1847H.Kamminga,M.W.Weatherall,The MakingofaBiochemist(I)FrederickGowlandHopkinsConstructionofDynamic BiochemistryMedicalHistory 40(1996):269292M.W.Weatherall,H.Kamminga, MakingofaBiochemist(II)TheConstructionofFrederickGowlandHopkins ReputationMedicalHistory 40(1996):415 436F.G.Hopkins,ThePractical ImportanceofVitaminesBritishMedicalJournal (26April1919):50710J.Needham, E.Baldwin(eds.),HopkinsandBiochemistry18611947:PapersConcerningSir FrederickGowlandHopkins,FRS, (Cambridge:W.Heffer&Sons,1949):5MRC MinutesII,(9September1920):113.
57
R.P.T.DavenportHines,J.Slinn,(1992):75.
MRCMinutesII,(12January1923):3.
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TheSexHormonesCommitteeincludedDr.F.H.A.Marshall(chair),Dr.V.
66 KorenchevskyattheListerInstitute,andDr.A.J.ParkesoftheNIMR.
Inadditiontoestablishingcommittees,theMRCfundedfurtherresearch:
67 WarringtonYorkes colleagues,Dr.A.AdamsandDr.F.Murgatroydtostudyanti
malarialremediesandpotentialtrypanocidesProfA.E.BoycottandProf.F.J.Browneat
68 UCHtostudy thebacteriologyofpuerperalinfection Dr.J.F.WilkinsonatManchester 69 RoyalInfirmaryforchemicalworkonperniciousanaemia Prof.W.W.C.Topleyofthe 70 UniversityofManchester (laterProfessorofBacteriologyattheLondonSchoolof
HygieneandTropicalMedicine)andProf.HenryStanleyRaper,ProfessorofPhysiology atManchesterUniversityreceivedfundingforworkfortheanaestheticscommittee,71
72 Prof.EdwardCharlesDodds attheMiddlesexhospitalforworkontesticularhormones 73 Dr.R.CruickshankattheUniversityofGlasgowforserumtreatmentofpneumonia and 74 DrDerekN.Dunlop ofEdinburghworkonmetabolism Prof.J.C.Meakinsatthe
UniversityofEdinburghwasgiventwograntstosupportDrs.J.S.MurrayandC.G. Lambie(fromMarch1923)andProf.R.T.Leiperperformedstudiesonimmunityof
64
MRCMinutesIII,(11April1930):73,74. MRCMinutesIII,(24October1930):150.
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drugswhentherewerenonaturalreplacementsforGermandrugssuchasSalvarsan, Veronal,andAspirin,despitetheoccasionalreluctanceofBritishdoctorstoacceptthe
79 qualityoftheBritishversions.
January1923tocollectinformationforthenutritioncommitteeonthediseasemortality
75
MRCMinutesIII(22March1929):54
ReforminMedicalEducationBritishMedicalJournal (1January1921):20.
79
MRCMinutesII,(27May1921):76.
270
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81 relatedtomigrationfromruraltoindustrialareas. Astatisticsdepartmentwas
oftheMRCprovidethebackgroundtowhypharmaceuticalcompaniesweresokeento collaboratewiththeMRC.
6.3TheABCMApproachtotheMRCforaClinicalTestingSchemein1922
Theextensionof theKeyIndustryActin1921toincludepharmaceuticalsand otherfinechemicalsofferedonlypartialprotectionforuncompetitiveBritish pharmaceuticalfirms.Whiletheywelcomednewrestrictionsontheimportationofdrugs fromabroadthathadnotbeenbiologicallytested,onlyclinicaltrialsinpatientscould offerconclusionsabouttheclinicalefficacyandsafetyoftheirownnewpowerful,andyet potentiallytoxicdrugs,butthesewerenotmandatory.TheFoodandDrugsActof1899 andDangerousDrugsActof1920onlyrequiredthestrengthandcontentofnewdrugsto bespecified.Therewasnolegislativerequirementtoproveefficacy.Intheorynothing preventedacompanyfromplacingnewproductsonthemarket.However,without supportingdatafromleadingpharmacologistsandcliniciansanewdrugwouldbeunlikely tobeacommercialsuccess. JoshuaBurn,theformerBurroughsWellcomeresearcher whowasresponsibleforbiologicalstandardisationattheNationalInstituteofMedical ResearchandthenatthePharmaceuticalSociety,latersummarisedthedifficultiesof performingtrials: Clinicalresearchworkisdifficultbecausetheexperimentalanimalisthe patient,whoisnotatthedisposaloftheexperimenter,andwhosewelfare
81 82
MRCMinutesII,(12January1923):6.
J.Beinart,TheInnerWorldofImperialSickness:theMRCandResearchin TropicalMedicineinJoanAustokerandLindaBryder(1989):109135.
271
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mustremain amoreimportantconsiderationthantheoutcomeofthe research.Norcanthepatientsusuallybecollectedinlargegroupslike 83 mice. Intheabsenceofclinicaltesting,manufacturingcompaniesinsteadfollowedmedical publicationsandwhenanewconceptormethodoftreatmentwasdescribedtheyrushedto produceadrugwiththerelevantcharacteristics.Examplesincludethemultitudeof antisepticsmarketedafterListersdiscovery,includingalsobismuthsalts,calomel, mercuricsulphate,salol,betanaphtholandnaphthalenetetrachloride,andtheplethoraof phosphates,hypophosphates,andglycerophosphates,whentheywereshowntodecrease demineralisationofbones. Furtherexamplesfollowedthediscoveryofvitamins.Clinical trialswerenotalwaysneededinsuchcasesasthecompanycouldrefertothescientific proofalreadyestablished.Thefirmswerejustprovidingtheirversionofaprovenactive ingredientandtheydifferentiatedtheirdrugsonpurityandstrength.Theproblemwith thisapproachwasthatthenewtherapywasnotexclusiveandcouldbepreparedbymany firms.Fornoveldrugs,pharmaceuticalfirmsneededatleastafavourableclinical opinionpublishedinamedicaljournal,evenifittookonlyafewpatientstoachievethis aim.Britishfirmsthathaddifficultyinarrangingclinicaltestsfeltthatiftheirproducts weregivenasealofapprovalfromtheMRC,thiswouldgivethemanadvantageover Germanfirms. ThefewBritishfirmsthatinvestedinsyntheticchemistryhadmajordifficulties arrangingforclinicaltrialsoftheirnewdrugsasmostBritishdoctorswerenot accustomedtodealingdirectlywithpharmaceuticalmanufacturersandremained suspiciousofBritishsyntheticdrugs.Previouslyclinicaltrialshadnotbeenperformed becausecompaniesweresimplymanufacturingextractsrequiredbyphysicianstotreat patientsaccordingtotimehonouredtraditions.Assemisyntheticorsyntheticdrugshad neverpreviouslybeengiventohumans,firmshadtheadditionalhurdleoffirstconvincing thescepticalmedicalprofessionoftheirpotentialvalue,whereaspreviouslytheyhad simplyproducedalkaloidalextractsorinorganicmedicinesofknownefficacythatdoctors requestedandhadprescribedfordecades.Physicianswerealsoawareofthe contemporarylegalpositionwhileitisthedutyofaphysicianorsurgeontokeepup
83
J.H.Burn,TheBackgroundtoTherapeutics(Oxford:OxfordMedicalPublications, 1948):preface.
272
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withtheadvancementmadebyhisprofessionitisalsohisdutynottoattempttoforge
84 aheadofitbytryingexperimentsonhisregularpatients.
ThefirstmeetingwiththeMRCtookplaceon15February1923followinga
87 memorandumfromWoolcock, secretaryoftheABCM,whichsummarisedtheproblems,
84
Quotedfroma1918legalencyclopediabyK.LawrenceAltman,WhoGoesFirst? theStoryofSelfExperimentationinMedicine(NewYork:RandomHouse,1987):12.
85
G.E.PearsontoW.J.UlneyWoolcock,(18December1922)andW.J.U. WoolcocktoM.R.C.,(19February1923),MRCFile1523.
86
87
BritishFineChemicalsBritishMedicalJournal (29April1922):666.
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workers,[and]theprofessionalpositionofmedicalmenwhomaybecome associatedwithmanufacturingfirms. Whenamanufacturerhadevolvedbyresearch,asubstancewhichwas believedtobeoftherapeuticalvalueithadtobefirsttriedbya pharmacologisttomakesurethatitwouldbesafeforclinicaltrials.Such pharmacologistswerescarceinEnglandandfew,ifany,hadassistantsin training.Thepharmacologistswerealsoengagedintheirownlinesof researchfromwhichtheydidnotwishtobediverted.Asaresultofthisitis onlybyaluckychancethatthemanufacturerscangetanewproducttried pharmacologicallyinthiscountryandcontinuouscooperationinalong researchsuchasthatwhichinthecourseofsomethinglike15yearsworkin 88 Germanyledto'Bayer205'issimplyoutofthequestioninEngland. Bayer205ortryparsamide(Germanin)wasanewGermandrugfortreatingsleeping
89 sickness. Itwassignificantnotonlyforitsmedicalimpact,whichwouldbelimitedto
MRCMinutesII,(17July1925):122,and(30April1926):63.
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existingremediesandcallingattentiontoanyunexpectedfeaturesinthe natureofitsaction.Itissafetosaythatsuchreportsareonlyobtainablein exceptionalcircumstancesinEnglandtoday.Whatusuallyhappensisthata medicalmanundertakestofurnishaclinicalreportandafterlongdelaysays thatowingtopressureofotherdutieshehasbeenunabletoundertakethe workortofinishareport,whichmerelystatesthatthedrugisorisnot satisfactory.Thisdifficultycanonlybeovercomeinthelongrunbythe provisionofmorepharmacologistsandexpertclinicalobserversandthis canonlybedonebythemedicalcollegesinthiscountrygivingmore attentiontothesesubjectsandencouragingstudentstospecialiseinthemat afairlyearlystageintheircareers.Butinadditiontothissomearrangement isrequiredwherebymanufacturerscanobtainasamatterofcourse, pharmacologicalandclinicalreportsonnewdrugs,justastheycanalready obtainreportsfromchemists,lawyersandotherprofessionalmenon chemical,legalandotherquestions.PerhapsthiscouldbedonebytheMRC formingapanelofpharmacologists,cliniciansandothermedicalexperts whommanufacturerscouldconsulteitherdirectorthroughtheCouncil.It ispossiblethattheCouncilcoulditselfarrangeforsomeofthisworkto doneinitsownlaboratoriesbutitwouldnodoubtbenecessaryto supplementsuchfacilitiesveryconsiderablyinordertocopeadequately withtheworkandtheformulationofapanelofmenwhomthecouncil considersuitableforsuchworkwould,itisthoughtbeofgreatassistance, notonlyasregardstheimmediatedifficultybutalsointhewayof stimulatinginterestinthesesubjectsandencouragingstudentstospecialise inthesedirections. 2)Professionalroleofmedicalmenwithmanufacturers Itisclearfromtheforegoingthatifthiscountryistotakeitsproperplacein chemotherapeuticalresearchandinthefinechemicalmanufactures,which shouldresultfromit,therewillhavetobeamuchcloserassociationof medicalmen(usingthatterminthebroadsensetoincludepharmacologists, physiologists,etc.)withmanufacturersthanhashithertobeenthecasein Englandandthequestionhasbeenraisedwhethermenwhothusbecome associatedwithindustrialfirmsforsuchpurposeswilllosecasteintheeyes oftheirprofessionalbrethrenandmayevenruntheriskofbeinglookedat askancebytheauthoritiesofthemedicalcolleges.Itisnoteasytostatethis difficultypreciselyandpossiblythenearestapproachtoaccuracymaybeto saythatthereseemstobeafeelingamongcertainmedicalmenthat professionalassociationwithafirmisregardedbytheleadersofthe medicalprofessionasnotquitetherightthing.Thisisaratherintangible matterandadmittedlydifficulttodealwithbutitwillberealisedthatina countrylikeEnglandwherethe'correctthing'inconductisafactorofno smallimportance,suchafeeling,ifitexists,maybeaseriousobstacleto progress.OnthismatteritishopedthattheM.R.C.maybeabletoafford manufacturerssomeguidanceandpossiblytoissuesomestatementonthe generalquestionsdealtwithinthismemoranduminwhichwouldbe incorporated,shouldtheyseefit,todoso,someexpressionofopinion, indicatingthattheywillbegladtoseeclosecooperationbetweenmedical 275
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expertsandmanufacturersforthecommonobjectofsecuringprogressin therapeutics.Inthisconnectionitmayperhapsbementionedthatthereare alreadyinexistenceinthecountryinstitutionseitherendowedorsupported bynationalfundswhichhaveontheirstaffseminentscientificandmedical menandwhichundertakepurelycommercialinvestigationsandworkin closeassociationwithindustrialfirms.Theprestigeofsuchinstitutions seemstobeinnowayinfluencedbysuchassociation,noristhestandingof theirstaffsaffectedandinviewofthisthereseemstobenoreasonwhythe directassociationofmedicalmenwithindustrialfirmsshouldactinany 91 waytotheirdetriment. Thestigmaofliaisonswiththepharmaceuticalindustryregardingadvertisingandselling ofdrugsremainedinBritainfollowingthecampaignsagainstthepatentmedicine producers.DoctorsreliedonLondonbasedconferencesandoneditorialswrittenbythe medicalelitefortheirinformationonnewdrugs.Onlyrarelyweredogmaticclaims substantiatedwithextensiveclinicaldata.IndividualcasereportspredominatedinBritish medicaljournals.Towhatextentthisreflectededitorialpolicy,thephysiciansprecept thattherapyhadtobetailoredtotheindividual,orthedifficultiesofarrangingtestsofnew drugsisdifficulttoassess.Tradenamesofdrugswerefrowneduponandtheroleofthe manufacturingcompany wasrarelyacknowledged. Clinicaltrialshadbeenperformedinthepastwithvaccinesandantitoxins,but
92 localhealthboardsorganisedtheseinaccordancewithGovernmentpolicy. Allofthe
offeredsalesanddistributionservicesforvaccines.Nowthatsomepharmaceuticalfirms
91
G.E.PearsontoW.J.U.Woolcock,A.B.C.M.,(18December1922),MRCFile 1523.
92
276
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weredevelopingtheirowndrugstheysoughtwiderinteractionswithmedicalresearchers andhavinglimiteddirectsuccesstheyhadturnedtotheMRC.
MRCagreedtotesttheextract,knownasinsulinaslongasnorestrictionswereplaced
95 uponthem.
oftheirthesiscasestudies.BothreferredtotheseminalstudybyLiebenau,thoughthis wasbaseduponalimitedappraisaloftheMRCsourcerecords,referringtoinsulinasa
94 95
M.R.C.MinutesII,(17November1922):375(8December1922):389.
Thefirstdiscussionsaboutinsulinwereon24March1922,MRCCouncilMinutesII, (21July1922):318.
96 97
277
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ProtestsappearedfromSirWilliamBaylissofUniversityCollege,London.104 The
98
H.H.Dale,H.W.Dudley,ReporttotheMedicalResearchCouncilofourVisitto CanadaandtheUnitedStates(30October1922):318,MRCFile1092/15.
101
MRCMinutesII,(21July1922):318Amethodofconcentrationofinsulin,granted toDudleyandtheCouncilMRCMinutesII,(25March1923):26.
103
278
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educationalist,ProfessorH.E.Armstrongalsosentastronglywordedletterofcomplaint
105 toTheTimesaboutthepatentingofmedicaldiscoveries.
bytariffsandFrancisCarrlaterfoughtagainstremovalofthetariffonDanishinsulinand
107 thepossibilityoflowpricedimports. Insulintariffswerediscussedupuntil1933,when
aparliamentarytribunalwasestablishedundertheSafeguardingofIndustriesAct. Insulinwasclearlyanimportantadvance,butitinvolvedacomplexextraction processandwithoutpharmaceuticalindustrysupport,supplieswouldhavebeenlimited. HoldingthepatentswouldenabletheMRC: toexerciseamoralcontrolovermanufacturersandwouldinducethelatterto submittoasystemofsupervision,asregardsthisproduct,whichthelawdoesnot enabletheCouncilatpresenttoenforce(and)wouldregulariseanddefinethe council'sauthority.Thereforemanufacturerswouldsubmittocontrolasper 108 Salvarsan. IthadalwaysbeenthepolicyoftheCouncilnottocountenancepatentingwitha viewtopecuniaryprofitandyettheyhadinthepastacceptedassignmentof patentrightswithaviewtosecuringcontrolinthepublicinterestandinspecial circumstancespromotedpatentingpurelyasadefensivemeasureagainstimproper exploitationofamedicaldiscovery theyhaddeclinedpatentsinthecaseof 109 Streptococcalantitoxinandscarletfever.
105
MRCFile1092,(30August1922).
J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):176BDHstatement (January1934),MRC1092.
108 109
ReportofTriptoAmerica,H.W.Dudley,(30October1922),M.R.C.File1092. MRCMinutesIII,(29April1927):56.
279
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TheMRCwerehowevercriticisedinsomequartersfortheirpolicy,forexample,Bayliss wrote:thereisastrongfeelinghereagainstpatentingtheproductsofvalueintheareaof
110 disease.
EarlytrialsofinsulinintheUSAhadgivenresultsofbrilliantpromisecreatinga hugedemandbeforetheactiveprincipleanditsmanufacturewereidentified.TheMRC cameunderpressuretoreleaseinsulinratherthantoperformfurthertests,butthey defendedtheteststhatweretopromote: whateverenterpriseororganisationisbestfittedforsecuringtheearliest productionoftheinsulinextractunderproperconditionsofsafetyand control.Inthiswaythenecessaryscientifictrialsofthetreatmentcanbe 113 mostreadilyobtained. TheMRCsecuredsuppliesofpancreasglands 114 andthiskeptthepriceofinsulinlow. Threealternativestrategieswereconsidered: a)Patentingthenlicensingouttovariousfirmswithspecificationofquality,safetyand priceandtestingattheNIMR.
110
SirWilliamBaylissInsulin.DiabetesandRewardsforDiscoveriesNature(10 February1923):18891.
111
280
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b)ProductionofinitialsuppliesattheNIMRorothernoncommercialcentres.
115 c)Studiesatselectedfirmseachwithlocalmanufacture.
TheMRCSecretarywrotetoBurroughsWellcome,BDH(actingtogetherwith A&H),Boots,EvansSonsLescher&Webb,andDuncanFlockhardtregardinginsulin
116 supplies. TheirpreferredchoicewasBurroughsWellcomeforThevastexperienceof
thesepeopleinmakingsuchpreparationsasadrenalin,iodothyroglobulin,pituitrin,etc. it
117 ismorelikelythattheywillhituponimprovements. Theyrealisedtherewouldbethe
withonlyonefirminLondontochooseitwouldhavetobeBurroughsWellcome,giving
119 themtheopportunitytobeaheadoftherestoftheBritishfirms.
delayingcommercialproduction,butonceproductionissueswereresolvedtheywereable
115
116 117
118
119 120
281
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AnInsulinCommitteewassetupandestablishedtrialsatMRCsponsored
123 laboratoriesthathadappliedforalicensetoperformtrialsinNovember1922. Fiveof
PatonrecommendedthatBurroughsWellcomeshouldbeinvolvedandtheymade
126 enquiriesaboutgainingalicenseatthestartofDecember1922. Afterinitial
discussionswithtenfirms,threeLondonfirmsestablishedcommercialproductionof insulinearlyinMay1923.FletchersatonacommitteewiththeMinistryofHealthto
127 discussthebestmeansofdistribution.
121
122
W.M.FletchertoW.M.F.Paton,(23November1922),MRCFile1092.
282
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Allen&HanburysandBritishDrugHousesworkedtogetherandBurroughs
128 Wellcomeworkedalone. Therewerealsosubsequentlythreefirmsinvolvedfromother
partsofthecountry,namelyBoots,EvansSons,Lescher&Webb,andDuncan
129 Flockhardt. Everybatchofinsulinhadtoundergoindependenttests,uponpaymentof
afeeandcouldnotbesolduntilcertified.HowevertheNIMRwereunabletocopewith allofthetesting,sofromJuly1924foratrialperiodofaround2months,British manufacturersperformedtheirowntestsontheinsulinthattheyproduced,withcontrol batchesbeingsenttotheNIMR.AsmallamountofUSinsulinwasbeingimportedbutthe UStestswere trusted.Forapreliminaryperiodallsaleshadtobedirectedthroughthe Council.Amaximumnetsellingpricewasfixed,andonlythenameinsulincouldbeused. NomisleadingorexaggeratedclaimsofefficacywereallowedandtheCouncilfurnished statementsonthemodeofadministrationandprecautions.Activityhadtobestatedin plainfigures,instandardunits,withabatchnumberandreferencetotestsandanominal
130 royaltywastobepayabletotheMRC. Bysettingdowntheserigorouscontrolsthe
128 129
H.H.DaletoW.M.Fletcher,(4May 1923):53,MRCFile1092.
W.M.FletcherletterManufactureofinsulin,MRCMinuteBookII,(17July 1924):109J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):170
131
283
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132
J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):175. H.H.DaletoW.M.Fletcher,(1January1923),M.R.C.Files1092.
135 136
284
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BritainwasfaraheadofGermanyintheproductionofhormonesandvitamins.Itwas wellinto19245beforelargescaleproductionofinsulinwasachievedinGermanyor
140 France,andthentheMRCalsoinhibitedtheimportationofinsulinfromBayer.
TheMRCremainedpreoccupiedwithinsulintrialsforthetwoyearsandresults
141 werepublishedintheirannualreports. Thearrangementoverinsulinworkedwell
139
140
MichaelBliss,(1983):165J.Liebenau,inJ.AustokerandL.Bryder(eds.), (1989):175.
141
285
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manufacturetocertainfirmsandtheirclearfavouritewasBurroughsWellcome.However, thebalanceofpowerintheBritishpharmaceuticalindustrywasshiftingsignificantly towardsBritishDrugHouses. Aswehaveseen,FrancisCarrwasalreadyawellknownfigureintheBritish pharmaceuticalmanufacturingindustry.HehadcollaboratedwithDunstanatthe PharmaceuticalSocietybeforetakingoverasWorksmanageratBurroughsWellcomein 1898.Havingestablishedamanufacturingcapacityforsemisyntheticdrugsandalkaloids, hemanufacturedSalvarsanin1914andwasheadhuntedtojoinBootstoestablishtheir manufacturingcapacityduringtheWar.ImmediatelyaftertheWarhewasenticedfora largesalarytojoinBritishDrugHouses.Ineachcasehewasabletoattractasignificant numberofhiscolleaguestomovewithhim.In1919hewaspartoftheABCMmissionto visitGermanfactoriesandin1921hecoauthoredatextbookthatoutlinedforBritish chemiststhemethodsofsynthesisingorganicdrugs.Hewasalsoanactivememberofthe SocietyofPublicAnalysts,andamemberoftheCounciloftheSocietyoftheChemical Industryfrom192023.Hehadpreviouslycontributedtosignificantlyimprovingthe manufacturingyieldofthyroxin,butitwashisachievementsinmakingBritainself sufficientininsulinthatbroughthimworldwidefame:F.H.Carr,whohasplayeda distinguishedpartinthedevelopmentoftheBritishfinechemicalindustry,closely
143 associatedwithearlyproductionofinsulininthiscountry, andhehasexhibited,asin
thenotablecaseofinsulin,averypracticalcapacityformasteringtheengineeringand
142 143
J.LiebenauinJ.AustokerandL.Bryder(eds.),(1989):171. TheFinancialNews(17June1926),ChemicalIndustryCongress,London.
286
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engineeringskillstoincreaseyieldsofinsulinby20fold.Thepriceofinsulinfellfrom25
145 shillingsto2shillings8dper10dosesover12months. Itfellfurther:Thescientific
industryofthiscountryhadreasontobeproudofthefactthatwithin18monthsofits introduction,productionhadincreasedsogreatlythatabalancewasavailableforexport
146 andtheoriginalpricedecreasedto1/11d.
theonlywaytoproperlytestdrugswasinthehumanbody,hencehisstrongurgefora definedsystemofclinicaltests. CarrbelievedthatdoctorsintheU.K.wereconcerned aboutpecuniaryinterestswithpharmaceuticalfirms,andalthoughFraseroftheMRC disputedthis,Carrarguedfortrialstobearrangedthroughacentralindependentbody.He suggestedthataftersuch officialtests,individualmedicalmenwouldbelessafraidof performingtheirownpersonaltrialsandofpublishingtheresults.Carrdescribedhow individualmedicalmengenerallymadetestsinGermany,wherethemanufacturersquoted findingsinadvertisements.OnlythepreviousyearaneditorialintheBritishMedical JournalreferredtomedicalresearchonnewremediesinBritainwherethosecarefulof
148 theirreputationsmuststepwarily.
144
TheTimes(16June1926),B.CarrarchivesIVcuttings,ImperialCollege.
145
DailyTelegraph (12July1927).F.H.Carr'spersonalarchivesattheImperial InstituteincludecuttingsfromtheNatalMercury (30June1927)andDailyNews Colombo(5July1927).Thepricesofinsulinwerekeptcloselyinlinethroughoutthis timeThePriceandUnitValueofInsulinAnnouncementbytheMRCBritishMedical Journal (22December1923):1232.BurroughsWellcomepricesfor100units(10doses) wereinitially25/,then17/8,12/6andwerereducedto6/9from25February1924andan extratradediscountof20%BDHandA.&H.reducedpricesonthesamedays.
147
287
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CarrgaveseveralkeynotelecturesonthestateoftheBritishpharmaceutical industryinthemid1920'sincludingtheStreatfieldMemorialLectureattheendof
149 1925. By1926BritishDrugHouseswereprobablytheleadingfinechemicalcompany
inBritain(aheadofBurroughsWellcomeandBoots.)Muchoftheirprogresscamefrom
150 thesuccessinmanufacturinginsulin,whichCarrrecountedinFebruary1926. Healso 151 playedaprominentroleinthemanufactureofvitamins. By1926Carrhadbeenelected
PharmaceuticalSocietyMeetingTheApplicationofScientificMethodtothe SolutionofIndustrialProblemsChemist&Druggist(12December1925):8358.
150
F.H.Carr,InsulinanditsManufacturetoRoyalSocietyofArts,(23February 1926)inB/CARRF.H.,CarrArchive,ImperialCollege.
151
F.H.Carr,VitaminsintheirRelationshiptoMedicalSuppliesChemist& Druggist(1926)89799.
152
F.H.Carr,ThePositionandProspectsoftheOrganicChemicalIndustryinthis CountryChemist&Druggist105.1(24July1926):170.
153
F.H.Carr,ChemistryintheProgressofMedicineChemist&Druggist106.3(9 July1927):233
288
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AlfredRenshawoftheLaboratoryofAppliedPhysiologyinManchestermadea pleaformultidisciplinarycollaborationbetweenbiochemists,medicsandorganicchemists andhequotedtheconclusionsoftheAmericanSocietyofChemistry: Medicalmenmustrealisethatthetaskofbuildingupnecessarilycomplex substances,whichaloneseemtohavetherapeuticvalueisamatterforcareful thoughtandpatientexperiment,thechemistsmustrealisetheintense difficultiesofobtainingandcorrelatingmedicalandclinicaldata,andabove all thecommercialorganisation,whichendorsessuchaproduct,mustbe preparedtowait,notmonths,butyearsforthefruitfulresults,whichmustof 156 necessityarisefromsuchacombinationofresources. Inparticulartherewasaneedtobridgethegapbetweenwhatitwaspossibletopreparein theresearchlaboratoryandinaproductionplant.HefeltthatBritainhadtobecome strongineverypartofthechainfromobservation,throughexperiments,development,
157 pilotplantscaleup,clinicaltestingandmarketing.
Ibid.
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ProgressofMedicine,Carrdescribedtheprogressmadeinsynthesisingadrenaline,
160 histamineandthyroxine, givinghisinterpretationofchemotherapyalongthelinesof
Ehrlich.Hereferredtothechangesundergoneinthebodybytrypanocidalagents,Bayer 205andFourneau309,bothcolourlessandthoughactiveinvivo,hadlittleinvitro activity,aswithbismuthandhecitedthedepoteffectsoflonglastingformsofbismuth andarsenicals,andtheeffectofsunlightonergosterol.Hefeltthat: progressliesinthedirectionofbiochemistryandmoreeffectiveworking contactbetweenindividualsinchemistry,bacteriology,physiologyand clinicalmedicinetoavoidoverlapping.Chemicalexperimentmustproceedin theveryclosestassociationwithanimalexperimentationandwithclinical trials.Therearemanyconditions,whichcanonlybestudiedinmanhimself andtheimportanceofproperlyorganisedclinicaltrialsandtheproperinter relationofalltheseelementsofprogresscannotbetoostrongly 161 emphasised. Hesawthisastherationalefortestingdrugsinman.Carrreemphasisedtheneedforboth pureandappliedresearchincollaboration,forthemajorityofantiinfectivecompounds developedhadbeenforprotozoalinfectionsforwhichanimalexperimentalmodels existed,suchasinthedevelopmentbyBargerofthequinolinederivative,plasmoquine,
158 159
290
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forward. Inadditiontohisworkinimprovingproductionmethods,Carrdevelopedtests
163 forthepotencyofthefirmsproducts,suchasether. Healsoexaminedthepotencyof
EversofMay&BakercomplimentedCarronhismodificationoftheonlypracticabletest
165 availabletodate. Heshowedthesuperiorityofhisfirmsproductsoverandabovethe
6.6MRCExtendedRoleinClinicalTrials: IndividualMRCSubcommittees
162
F.H.Carr,EtherclonusBritishMedicalJournal (8October1927):664.
164
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167 TheMRCcontinuedtoaddfurthersubcommitteesasnewopportunitiesarose.
SomewereestablishedundertheauspicesofotheracademicbodiesbutunderMRC guidance,suchasthatappointedbytheObstetricSectionoftheRoyalSocietyof
168 Medicinetoevaluatepituitaryextracts. Inadditiontosupportingworkoncancer, 169 previouslydescribed,theMRCalsosupportedresearchbytheColonialOffice. MRC
workwaslikelytorevolutionalisenotonlytuberculosis,butalsootherbacterialdiseases.
167
MRCCouncilMinutesII,(22July1921):112.
292
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Althoughthetreatmentturnedouttobenomoreeffectivethanavailabletherapies,Dreyer
172 wasappointedDirectoroftheStandardsLaboratoryinOxfordinFebruary1924.
askedbyhimtoarrangeclinicaltrialswithaviewtoconfirmingresultsinDenmark. FletcherplannedatrialalongthefollowinglinesinDecember1924.Herecountedthat (Moellgaard): isprovidingsuppliesofthegoldcompoundandoftheserumtobeusedin conjunctionwithitforthepurposesofthisworkandnonewillbeavailablefor generalusebytheprofessioninthiscountryuntiltheseconfirmatorytrials havebeensuccessfullyperformed.Thetreatmenthasnotbeenfoundsuitable forcasesofsurgicaltuberculosisanditisproposedtolimitthepresentstudies tocasesofpulmonarytuberculosis,towhichsomecasesoftuberculous meningitismaybeaddedineachoftheclinicsdiagnosishasbeenconfirmed byproofofthepresenceofbacilli.174 TheCouncilsubcommitteesuggestedrecruitingnotmorethantencasesineachcentre,
175 restrictingcasestopulmonarytuberculosisprovenbythepresenceofbacillus.
MRCMinutesII,(22February1924):21.
173
W.M.FletchertoArthurEllis,(1December1924),MRCFile1380/3.
175
293
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176 ElliottatUCH,G.MarshallatGuys,DrL.S.T.BurrellatBromptonHospital.
SanochrysinwassenttoDrGeoffreyEvansatSt.BartholomewswhoinvolvedF.R. FraserandC.F.HarristoProf.FrederickLangmeadatSt.MarystoProf.Hugh
177 MacLean, achemicalpathologistatSt.ThomasHospital:DrF.R.E.HeafatWarwick
appreciatedthedifficultiesconnectedwiththisinvestigation.CertainlywhenIpromisedto
180 carryoutthetestsIdidnotappreciatethemmyself.
Researchershaddifficultydistinguishinganyeffectsoftherapyfromthevariable
181 backgroundcauseofthedisease. Dr.Sechar,presumablyrepresentingtheDanish
Institutions.Ifontheotherhandonlyearlycaseswithlittletissuedamagearetreated,the resultslookedgood,butthensodidothertherapies.MacLeanfinallygaveananecdotal
176 177
W.M.FletchertoH.A.Ellis,(1December1924),MRC1380/3.
MacLeodhadbeensenttoFrancebytheMRCin1915toinvestigateacutetrench nephritis.J.AustokerandL.Bryder(eds.),(1989):66,212.
178 179
MRCFile1380/3,(17March1925).
H.MacLeantoW.M.Fletcher,(8February1925),SanochrysinMRCFile 1380/3.
181
L.Bryder,TuberculosisandtheMRCinJ.AustokerandL.Bryder(eds.),(1989): 12MRCFiles1380/3onsanocrysin.
182
H.MacLeantoW.M.Fletcher,(8February1925),SanochrysinMRCFile 1380/3.
294
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In1925theMRCreportedstudiesinwhichtheyhadcomparedquinineand
187 quinidinefindingthelatterfarsurpassesothers. However,upto1925themajority
ofnewproductsfromindustrywerevariantsofalreadyavailabledrugsandtheMRChad littleinterestinthem,preferringtoconcentrateonimportantphysiologicalquestions,
188 hormonalextracts,tropicalmedicineandstandardisationofbiologicaldrugs.
183
H.MacLeantoW.M.Fletcher,(8February1925)forquotes,andfinalreport(27 March1925),MRCSanocrysinFile1380/3.
184
H.J.MacLeantoW.M.Fletcher,(8February1925),SanochrysinMRCFile 1380/3.
186
In1922thefirstsuchM.R.C.reportwaspublishedJ.H.BurnandH.H.Dale, ReportonBiologicalStandards(I)PituitaryExtractsMRCSpecialReportSeries69
295
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fromtheDSIR.AttheCouncilmeetingof22October1926,aCommitteewasestablished jointlywiththeDSIRtoreportbeforeMarch1927onthescopeofworkrequiredin
193 Chemotherapy. In November1926theABCMGeneralmanager,W.J.U.Woolcock
MRCCouncilMinutesII,(2October1926):151.
296
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themtestedclinically.Myrecollectionisthatthequestionofinsulinbecame 194 veryprominentjustatthattimeandnothingfurtherwasdone. Fletcherrepliedthat: TheMRChaveforlongbeenanxioustoseebetterprovisionmadefor coordinatedresearchinchemotherapyandtheyhavehadthisunderdiscussion 195 withtheDepartmentofScientificandIndustrialResearch. HandwrittencommentsinthemarginofthisfilebyLandsboroughThompsonoftheMRC confirmedtheprincipalreasonsofwhythecollaborationontrialsofnoveldrugshad faltered(lackof)clinicalworkers,shortageofpharmacologists,medicalethics,anduse
196 ofanimals. Thistiedinwithongoingcontroversiesrelatingtodoctorsputtingtheir
197 namestodrugadvertisementsandtoarticlesinthelaypress. TheCouncilrespondedin
194
W.M.FletchertoW.J.U.Woolcock,TherapeuticTrialCommittee,(19November 1926),MRCFile1523/15.
196
A.L.ThompsonhandwrittennotesonW.J.U.WoolcocktoW.M.Fletcher, TherapeuticTrialCommittee,(17November1926),MRCFile,1523/15.
197
M.R.C.CouncilMinutesIII,(15July1927):155.
297
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ChristopherH.AndrewesbecamesecretaryoftheChemotherapyCommitteeinJanuary
204 1928. TheMRCprovided2,800totheDepartmentofScientificandIndustrial
Researchtoperformresearchinsyntheticchemotherapysothatpromisingcompounds
205 weretobeputforwardtoclinicaltrialsattheteachinghospitalsonaninformalbasis.
TheChemotherapy Committeealsoaimedtoassistwiththebiologicalandclinical testingofsyntheticcompounds,preparedattheNIMRbyHaroldKingandhiscolleagues. Theynotedthedesirabilityofprovidingfacilitiesforclinicaltrialsofnewremediesunder statedconditionsagreedbetweenthejointcommitteeandrepresentativesofABCM.Its guidelinesforhandlingapplicationsfortestnewdrugswere:thatdetailsoftheapplicant wouldnotbeprovidedtothosedoingthetesting,andthattheCouncilhadtherightto refusethetestingofanyremedieswithouthavingtostateareason.Theapplicanthadto giveanundertakingthatnoalternativetrialarrangementswouldbemadeuntilthe Committeetrialswerecomplete,andthenatureandcompositionofthecompoundshadto bedisclosedinconfidencetogetherwithdetailsofanyrelevantpublications,experiments carriedoutinthemanufacturersownlaboratoriesandthepatentsobtainedorappliedfor. ThearrangementsfortestingwereentirelyamatterbetweentheCommitteeandthe expertsundertakingtheresearch.TheCommitteedecidedthattheywouldnotpublish
200
MRCMinutesII,(22October1926):151MRCMinutesIII,(15July1927):127 (14October1927):155MRCMinutesIII,(11November1927):181.
204
TheD.S.I.R.laboratoryworkwastobeperformedbyProf.R.Robinson,Prof.G. Barger,andDr.G.J.Morgan.M.R.C.MinutesII,(1927):127,155,187,227.
298
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informationifitmadenoscientificcontributionandmightcausedamagetotheinterests oftheapplicant.Allexpenditurehadtobemetbytheapplicant,butiftheexperts proposedteststhatrequiredsignificantexpenditureonequipment,salariesortravelling expenses,detailsofproposalswouldbesenttotheapplicantforconsideration. TheChemotherapyCommitteeinitiallyarrangedtestsofantihelmintics, antimalarials,andtrypanocidals,whichfittedinwellwiththeresearchinterestsofthe MRCandtheirTropicalInstitutes.InJune1927ajointColonialMedicalResearch Committeewassetup,combiningmembershipoftheMRCwiththeColonialOffice.The chairwasRightHon.WilliamG.A.OrmsbyGoreandhisdeputywasSirGeorge Maxwell,togetherwithDr.JohnWilliamWatsonStephens,whowasoriginallybasedat theTropicalMedicineInstituteandperformedresearchonmalariaandblackwater
206 207 208 fever, SirLeonardRogers ,Dr.AndrewBalfour,Dr.CharlesTodd ,Dr.PhillipE. 209 210 MansonBahr ,Dr.CharlesM.Wenyon ofBurroughsWellcome,andMRCSecretary, 211 WalterM.Fletcher.
MRCCouncilMinutesIII,(29April1927):58,(24June1927):101. 299
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300
RoyalInfirmary,theSalfordRoyalandAncoatsinManchesterbuttheresultswere
216 patchyandthemethodsemployedtoobtainthemoftenlessthanrigorous. Despitethe
212
213
214
215 216
300
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introductionofasecondversionknownasSynthalinB,therewerecontinuedproblemsof
217 livertoxicity.
tosetuptrials.AperniciousanaemiacommitteeincludingElliott,Dale,andFraserwas
219 appointedtoarrangetrialsofthisnewlivertreatment. FrancisFraseroftheMRCand
217
MRCCouncilMinutesIII,(15July1927):156.
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002):164198.
301
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302
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002):175. C.C.Booth,ClinicalResearchinJ.AustokerandL.Bryder(eds.),(1989):318.
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002):171.
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desiccatedHogstomachfortreatingperniciousanaemia.Between19301931therewere alsoseveralpublishedreportsofsuccessinthetreatmentofperniciousanaemiabyliver
228 extracts,aswellasHogsstomach.
226
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002):1834.
228
J.F.Wilkinson,PerniciousAnemia.PreliminaryReportontheResultsObtained withCertainPreparationsoftheStomachBritishMedicalJournal (8February 1930): 3345J.F.Wilkinson,TreatmentofPerniciousAnaemiawithHogsStomach,Reportof 108casesBritishMedicalJournal (17January1931):8591C.S.D.Don,C.E.Jenkins. HogsStomachin PerniciousAnemia(24January1931):1589C.S.D.Don,C.E. Jenkins,OvarianHormoneBritishMedicalJournal (30May1931):940:TheValueof theLiverinTreatmentofAnemiaBritishMedicalJournal (4April1931):5845inwhich Wilkinsonreported140casesincluding108treatedfor6monthsormoreandnosingle casefailedtorespond.
229
MRCMinutesIII,(25October1929):167MRCMinutesIII,(16May1930):94.
303
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TherapeuticTrialsCommittee,despitethefactthatitwasstartedbeforetheCommittee
230 wasestablishedin1931.
TherewereotherapproachestotheMRCforclinicalstudies,includingone
231 acceptedfromLeverBrotherstohavetheirconcentratedvitaminApreparationtested.
230
D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945. Expertise,theStateandthePublic,(Cambridge:PhDthesis,September1997).
231
MRCMinutesIII,(11April1930):51.
232
ABCM,BritishChemicals:TheirManufacturersandUses(London:ABCM,1927 &1929&1931)inScienceMuseumArchive.
304
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KeyIndustrydutyhasbeeninstrumentalinpromotingthedevelopmentofthisimportant
234 keyindustry.
OfficeandpartlybytheWPRLandalthoughresultswerefavourabletherewasno
237 publication. Pearsonalsocommentedthat:
234
ABCM(London:ABCM,1927,1929,1931). A.J.P.Taylor,EnglishHistory191445(Oxford:ClarendonPress,1988):287297.
235 236
Bulbocarpainewasanisoquinolinealkaloidusedtotreatexcessivemovementsand spasms,T.A.Henry,(1939):17475,304,311.
237
G.E.PearsontoABCM,(24November1930),FileoftheTTC,MRCFile1523/15.
305
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butattemptstohaveKurchibarkandthealkaloidalconessineorHarmine 238 testedforParkinsonism,rigororparalysisandmalaria,ledtotheirfailure. J.DavidsonPrattwhohadledtheABCMsince1928forwardedtheletterfromPearsonto theMRC.Hewrote: TheABCMis,asyouknow,veryinterestedintheproblemofclinicaltesting ofnewmedicinalproductsandfirstraisedthequestionwithyouin1926(sic) theAssociationsubmittedvariousproposalsonthissubjectandthesewere discussedatyourrequestwiththenewlyformedChemotherapyCommittee whenthemainfeaturesofasuitableschemewereagreed.Thescheme,has not,howeverachievedallthatwasintendedandthedevelopmentofnew medicinalproductsisbeingseriouslyhandicappedbytheinadequacyofthe facilitieswhichareavailableinthiscountryforproperclinicaltests.The Associationfeelsthatthetimeisripeforafurtherefforttodevelopasuitable systemandwouldbegladifthememberswhoarevitallyinterestedinthe subjectcouldhaveanopportunityoffrankdiscussionofthewholeproblem withyourcommitteeinthehopethatbycooperativeactionitmaybepossible todeviseaschemeofclinicaltestingwhichwilleliminatetheobstacles,which areatpresentretardingthedevelopmentofnewmedicinalproductstothe 239 nationaldetriment. Afurtherapproach totheMRCwasrecordedandtherecognitionofthecontinued
240 problemsonbothsidesstimulatedfurtherdiscussions. Prattfollowedupwitha
furtherletterandaformalmeetingbetweentherepresentativesoftheABCMandthe
241 MRCtookplaceon16February1931. TheMRCmemberswereElliott,Fraser,Dale,
Fletcher,andLandsboroughThompson.ThecompanyrepresentativeswereFrancisCarr
238
J.DavidsonPratttoWalterMorleyFletcher,(28November1930),MRCFile1092, TTC1523/15.
240 241
ThemeetingwasrecordedintheMRCMinutesIII,(16January1931):4. J.D.PratttoW.M.Fletcher,(26January1931),MRCFile1092.
306
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WalterFletcherrecalledthattheCouncilhadbeeningeneralagreementabout arrangingstudiesfortheABCMin1927,but"ithadnotbeennecessary,intheabsenceof
242
FrederickWilliamGamble,encounteredbrieflyinchapter2whenhejoinedA&H asapharmacist.SincethenhehadbeeninvolvedincommitteesoftheLondonChemists AssociationandthefirstPharmaceuticalCodex(19031907)andinrevisionsofitin 1911and1923,theyearinwhichhechairedtheBritishPharmaceuticalCongress.Hewas aBoardmemberofAllen&Hanburysfrom1913andhadageniusforfriendlyrelations withthemedicalconsultants.Between192528GamblewasontheCounciloftheSociety oftheChemicalIndustryandin1930waselectedfirstchairmanoftheWholesaleDrug TradeAssociation(theforerunneroftheABPI)Mr.G.E.Pearsonsalesmanagerof BurroughsWellcomeMr.R.W.E.Stickings,WorksmanagerofMay&Baker,J.Slinn, AHistoryofMay&Baker18341984 (Cambridge:HobsonsLtd.,1984):122,125,128, 142,150,156Mr.J.DavidsonPratt,generalmanagersince1928andsecretaryofthe ABCMTherapeuticTrialsCommitteeMRCFile1092.
243
IwasunabletofindanydetailsaboutDr.H.A.MitchellofEvansSons,Lescher& Webbandhedoesnotfeatureanyfurther.
245
307
TheCampaignforClinicalTrials
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Itdesiresfullcollaborationwiththemedicalprofessioninsuchmattersand hasforsometimebeenworkinginclosetouchwiththeChemotherapy CommitteeoftheMRCandwiththeColonialResearchCommitteeinthe productionofnewsubstancesrequiredforextensiveclinicaltrials.Itishoped 250 practitionerswillsupportBritishindustry. Inordertobeginthenecessaryarrangementsfortrials,Prof.ThomasElliottenquiredof theABCMwhatthelargestnumberoflikelyrequestswouldbeinthecourseofayear. Hepointedoutthatclinicaltestingofanewremedymustatleasttakeaperiodofweeks ormonths,particularlyasitmightbenecessaryforagivendrugtobetestedbyseveral
251 differentclinicians.
TherenewedcallsforasystemoftestingBritishdrugscameasa'BuyBritish' campaignwasledbytheGovernment,EmpireMarketingBoardandthePrinceofWales: OnNovember16theEmpireMarketingBoardislaunchingacampaign. EveryretailerisaskedtoassisttofurtherBritishtradeandemployment.The CampaignhastheactivesupportoftheAssociationofBritishChambersof Commerce,theConfederation ofBritishIndustriesandseveralotherbodies. 252 ForeignproductsshouldfindnoplaceinBritishmateriamedica. Themedicalprofession,whosuggestedthatdoctorsshouldalsoPrescribeBritishreadily
253 tookupthebait. Aphysiciandescribinghimselfsimplyas'Countryman'wrote:
248
ReportofJointMeetingbetweentheMRCandABCM,(16February1931),MRC File1092oftheTherapeuticTrialsCommittee.
249
ReportofJointMeetingbetweentheMRCandABCM,(16February1931),MRC File1092oftheTherapeuticTrialsCommittee.
250
308
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6.11FormationoftheTherapeuticTrialsCommitteein1931. TheChemotherapyCommitteefailedtomeettheneedsoftheABCMmembersand focusedtoomuchontropicalmedicinewithstudiesoverseas.TheBritishpharmaceutical firmsstillhadnomeansbywhichtogetcliniciansinBritaintotesttheirnewdrugs.It wasalwaysassumedthatanorganisedsystemoftestingexistedinGermany,thoughthis probablywasnotthecaseandGermancompanieshadtoarrangetheirownstudies. However,astheyhadnodifficultyingettingtrialsperformedbyGermandoctors,this gavethemacompetitiveadvantage.CarrwaslaterabletoprovideevidencethatBayers scientificdirectorDr.Mertensin19235headedagrouporganisingtheirclinicaltrialsin Germanyandanotherforsalespropaganda.Theformerincludedfivephysicianssplit betweengeneralandtropicalmedicine.Trialswerecarriedoutfirstby14external clinicians,andifpromising,theprogramwasbroadenedover34years,thoughlessthan 5%oftheproductsstayedthecoursetobeissued.Applicationwasthenmadetothe
255 Governmentbutpermissionwasusuallygranted. Germandoctorsdidhoweverraise
concernsaboutthesafetyofnewdrugsafterawidelyreportedtragedyoccurredinLbeck in1930,whenmanychildrendiedandwereinjuredafteradministrationofcontaminated
256 BacillusCalmetteGuerin(BCG)vaccinetonewbornbabies.
254
TheLbeckTragedy BCGBritishMedicalJournal (21February1931):334M. C.G.Israels,A.D.MacDonald,ThePharmacologyofPeracaineBritishMedical Journal (28November1931):986988,TheBCGTragedyatLbeckBritishMedical Journal (28November1931):1016S.R.Rosenthal(ed.),BCGVaccine:Tuberculosis Cancer(Littleton,Mass:PSGPublishing,secondedition1980):358L.BryderinJ. AustokerandL.Bryder(eds.),(1989):1011.
309
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ThereweresimilarconcernsintheBritishmedicalliteraturein19301when
257 Bayer'sanaesthetic,Avertin,wasassociatedwithtoxicjaundice. Oneofthemain
reasonsforthedelayinestablishingclinicaltestingofnewdrugsinBritainwasthe relativepaucityofnovelchemicalsestimatedtobesixperyearasstillmostofthenew
258 syntheticdrugswerestillfromGermany. SirWilliamWillcox,physiciantoSt.Mary's
andHomeOfficepathologistwrote: Itshowedhownecessaryitwasthat,beforetheywereplacedonthemarket, thesedrugsshouldbesubmittedtocarefultoxicologicalandtherapeutictests onthehumansubjectaswellasonanimalsThechemicalmanufacturing industries(were)...dailylaunchingimperfectlytriedcomplexorganicdrugson themarketandthesystemoftestingdrugswas"unsatisfactory,exposingthe peopleofthiscountrytogreatdangerfromthetakingofnewdrugsadvertised 259 aspossessingwonderfulcurativeproperties". Asaresultofthegrowingconcerns,modificationsweremadetotheTherapeutic SubstancesAct,requiringwithdrawalofallofabatchfromsaleifitfailedtomeet
260 standards,andtheActcameintoforceon25July1931.
SirWilliamWillcox,"ControlofDrugs:AWarning",BritishMedicalJournal,(4 April1931):597TheChoiceofanAnaesthetic(14February1931):2656Avertin Anaesthesia(21February1931):330AvertininAnaesthesiaBritishMedicalJournal (20June1931):1095F.B.Parsons,AvertinBritishMedicalJournal,(4October1930): 5547F.B.Parsons,AvertinanaesthesiaBritishMedicalJournal (1November1930): 756FrancisE.Shipway,AvertinAnaesthesiaBritishMedicalJournal (8November 1930):799BasilHughes(Bradford),AvertinAnaesthesiaBritishMedicalJournal (22 November1930):887.Over100,000narcoticdoseswereplacedatthedisposalofclinics beforemarketing.
258
TherapeuticSubstancesActH.H.DaleArchives93HDBox21.2.129.
310
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1931,withtheaimofsecuringasystemofclinicaltestingoftheirnoveldrugs,including synthetics.Afterthefirstapproachattheendof1922,theMRCandthecompanies becamepreoccupiedwithinsulinproduction.Quiteapartfromtheapparentclinical efficacyalreadyseeninNorthAmericawithinsulin,theMRCheldthepatentsfortheUK andtheycouldcontrolthedistribution.Asecondapproachwasmadein1926aroundthe timewhentheMRCwasembarkingonthediscussionswiththeDSIR,whichwereto resultintheTherapeuticSubstancesActof1925.AChemotherapyCommitteewas established,reflectingthenewfocusoftheMRCandDSIRfollowingthediscoveryof Bayer205inGermany.Thereremainedaseriesofothercommittees,foranaestheticsand soon.OneofthereasonsforthefailuretoestablishtheTTCearliermayhavebeensimply thatitwasestimatedbytheABCMthattherewouldonlybehalfadozennewproducts eachyear.Studiesofantiseraandantitoxinswerequitedifferentandwererelativelyeasy toorganisethroughtheBoardofTrade. ThischapteralsosawthecontinuedascendancyofFrancisCarr.Hefinishedthe WarwithhonoursandwasgivenaprestigiousjobatBritishDrugHousesandwentonto fameforhissuccesswiththyroxinandinsulinproduction.By192627hewasthe influentialPresidentoftheSocietyfortheChemicalIndustryandcampaignedforbetter trainingofchemistsandasystemofclinicaltrials.TheChemotherapyCommitteeof1927 didnotmeettheManufacturersneedsandtheABCMcampaignedoncemoreforaclinical trialsystemin1930.Theyweresuccessfulthistime,in partduetothetimingoftheir approachinthemidstofharsheconomicconditionsandagainstabackgroundof increasinggovernmentinvolvement.ThefollowingchapterevaluateshowtheBritish companiesusedthenewTherapeuticTrialsCommitteeandattemptsalsotoassess whethertheavailabilityofaclinicaltestingsysteminfluencedtheirstrategyofdrug development.
311
BurroughsWellcomeStrategyintheInterwarPeriod.
312
CHAPTERSEVEN:BurroughsWellcomeStrategyintheInterwarPeriod 7.1Introduction. Aftertheendofhostilities,firmslikeBurroughsWellcomethathadcommittedto producingsyntheticandotherGermandrugs,hadtomakedifficultchoicesaboutdirections oftheirfutureresearch.Havinglostseveralkeymembersofstaffduringthewar, BurroughsWellcomesufferedfurthersignificantstafflossesimmediatelypostwar.Forthe firmthatalreadyproducedantitoxins,vaccines,syntheticdrugsandalkaloidal extracts, thereweresoontobefurtherstrategicchoicesasorganextractsandvitaminscameinto prominence.Wouldtheyreturntoimportingdrugs,ratherthandiscoveringtheirownand wouldaBurroughsWellcomeTabloidbrandofeachnewmedicinebepreparedorwould they specialise? InthissectionIevaluatesomeofthefactors,whichmayhaveshapedtheirpolicy. ThosethatIhaveidentifiedincludethechangingmarketpostwar,thefiscalandregulatory environment,thesizeandscopeoftheirownmanufacturingandtestingfacilities,andthe availabilityofresearcherstoperformclinicaltrialsontheirnewdrugs.Inordertoaddress theseissues,BurroughsWellcomemovedtowardsamoreformalmethodofdefining companystrategy,intheformoftheirScientificandTechnicalCommittee,establishedin 1925:thischapterisbasedaroundtheminutesofthiscommittee. 7.2StaffChangesandFacilities. InthepasttwochaptersIhavehighlightedsomeoftheproblemsfacedby BurroughsWellcomeduetothelossofexperiencedstaff,particularlychemistssuchas Carr,Ewins,Barger,andPower.On22February1919,Pyman,headoftheWCRL, becameProfessorattheCollegeofTechnologyinManchesterandaFellowoftheRoyal
1 Societyin1920. Dr.ThomasAndersonHenry,whotookoverasDirectoroftheWCRL,
hadstudiedthechemistryofalkaloidsatthePharmaceuticalSocietyfrom1893andat
2 ImperialCollegefrom1896.
H.King,FrankLeePymanObituaryNoticesofFellowsoftheRoyalSociety 4 (1944):681697.
2
Dr.ThomasAndersonHenry(18731958)servedontheBritishPharmacopoeia Commission,andthecommitteesoftheBiochemicalSocietyandChemicalSociety,L.G.
312
BurroughsWellcomeStrategyintheInterwarPeriod.
313
Asdescribedinthelastchapter,inMarch1919HaroldKing,anotherexperienced chemistleftBurroughsWellcometojoinDaleattheNationalInstituteforMedical
3 Research. RobertR.Baxterwhohadsynthesisedpilocarpine,Kharsivan,Salolandvarious
AlfredLouisBacharach,aCambridgegraduatefoodchemist,whohadworkedat
5 theWCRLandAnalyticaldepartmentsince1915,departedinJanuary1920. Bacharach
wasintroducedinthelastchapterwhenhejoinedNathans,aforerunnerofGlaxo,because
6 hedislikedhistediousdailyjourneyfromHampsteadtothenewsiteatDartford. Robert
WF:YLBox46,WorksHistory.
R.P.T.DavenportHines,J.Slinn,Glaxo:AHistoryto1962(Cambridge:Cambridge UniversityPress,1962):47,7172WF:Box25,WorkRecords.
7
FacilitiesforChemicalWork,(23December1926),STCWF:S/G/49.
313
BurroughsWellcomeStrategyintheInterwarPeriod.
314
TherewerealsofurtherchangesattheWPRL,whichhadalreadylostDale, Laidlaw,Burn,EwinsandBarger.A.F.WatsonsucceededPercivalHartleyasHeadof
8 Biochemistryin1921,asHartleydepartedfortheNIMR. Inordertoreplacesomeofthe
OBrien,abacteriologistjoinedfromtheListerInstitute,asdidG.S.Walpole,andtheir
10 mainfocuswasonvaccines. OBrienwasresponsibleforthedailyrunningofthe
In1920BurroughsWellcomemovedtheWPRLfromBrockwellHall,HerneHillto
12 a108acresiteatLangleyCourt,Beckenhamcosting30,000. Newfacilitieswere
establishedatTempleHill,includingachemicalsection,watertower,boilerhouse,and
H.J.Parish,WF:85/20:2,chapter5.
OppositiontoProposedLaboratoryChemist&Druggist94.3(14May1921):35 WPRLChemist&Druggist94.3(11June1921):61.
314
BurroughsWellcomeStrategyintheInterwarPeriod.
315
materiamedicafarmanewexploratorylaboratorywasopenedinMay1923andchemical
13 manufacturingwasmovedtoTempleHillinJuly1925.
Wellcomewoulddemandthousandsofpoundstopayforhisanthropologicalcollections
19 acquiredoverseas.
7.3TheScientificandTechnicalCommittee.
13
15 16 17
18
315
BurroughsWellcomeStrategyintheInterwarPeriod.
316
Intheperiodimmediatelyfollowingthewar,BurroughsWellcomeshapedtheir futureaccordingtothedemandsofchangingmarketsandregulatoryconstraintsratherthan bysettingdownaspecificpolicy.AttheendoftheWar,productionofsomeGerman drugssuchasphenacetinceased(inJanuary1921),asGermanpatentswerereinstated. Drugsthathadbeenneededforthewarwererequiredinsmallerquantitiesbutexport marketsthathadbeencompromisedbythewarwerereopened. Aftertradedeterioratedin1921,BurroughsWellcomestruggledtodecidewhether theyshouldreturntotheirroots,ortofollowthesyntheticapproachtakenduringtheWar. However,theywerenotfullypreparedtoinvestinthelongtermresearchasperformedin Germany,andsotheywereleftwiththepickingsfromcopyingdrugsoutofpatent, chemicallymodifyingthosethatremainedpatentprotected,andproducingsemisynthetic versionsofnaturalextracts.Theonly'new'productsmarketedimmediatelypostwarby BurroughsWellcomewereMenthofax(September1920)andMoogrol(July1921),and
20 theseanaleptics(stimulants)wereonlycopiesofdrugsalreadyavailableonthemarket.
19
H.J.Parish,WF:85/20:2chapters5,6MinutesoftheWellcomeTrustees(23 April1935).
20 21
A.W.Haggis,TypescriptHistoryoftheWorks,WF:85/20:2.
R.A.OBrientoG.E.Pearson,(16January1925),WF:S/G/49.ResearchReports, ScientificandTechnicalCommitteeNotesofMinute(s)andCorrespondence,(January
316
BurroughsWellcomeStrategyintheInterwarPeriod.
317
H.J.Parrish,ClinicalResearchonDiphtheria(I)(192240),TheWellcome ResearchLabsandImmunology,chapters34,6,WF:85/20/2.
24 25
ThefirstmeetingoftheSTCwason13February1925,WF:STCS/G/49.
H.J.Parrish,TheWellcomeResearchLabsandImmunology,chapter8,WF: 85/20/2.
317
BurroughsWellcomeStrategyintheInterwarPeriod.
318
HanburysandBritishDrugHousesandtheirfirstcommercialproductionofinsulinwas
26 notachieveduntilSeptember1924.
Occasionally,physiciansapproachedthefirmwithspecificrequests,suchasone whoaskedforadrugforanaemia,andtheyprovidedferriccacodylateanotherwanteda
29 reallyreliabledrugtoactasasedativeinepilepsy. Theserequestshadtobemanaged
efficiently,sothateffortswerenotwastedpreparingsmallbatches.Theoppositesituation alsooccurredwhenBurroughsWellcomefoundtheymadetoomuchofadrugsuchas
26
H.A.D.JowetttoG.E.Pearson,(15January1925):Arequestalsocamefor concentratedvitaminA,STCMeeting,(20January1925),WF:STCS/G/49.
318
BurroughsWellcomeStrategyintheInterwarPeriod.
319
hordenine(anhaline)analkaloidisolatedfrombarleymaltgerms,andcharacterisedby
30 Bargerin1909andsoneededtofindanoutlet. ThephysiologistsattheWPRLwere
taskedwithfindingalternativeuses.Thissubstancehadpsychicandmotorexcitation effectssimilartoephedrinebutathighdosesiscouldcausedeathbyinhibiting
31 respiration.
Carr.HehadalsobeenaresearchassistanttothechemistWilliamA.TildenattheRoyal CollegeofMinesinLondon.RepresentativesoftheChemicalSocietycontacted
30
31 32 33
319
BurroughsWellcomeStrategyintheInterwarPeriod.
320
BurroughsWellcome(andotherfirms)earlyinJune1925withanofferfromtheDSIRto collaboratemorecloselyindevelopingnewchemotherapeuticdrugs.Followingthe descriptionofBayer205therewasarenewedinterestinchemotherapyandthegovernment waspreparedtoinvestfurtherresearchmoneyintoasearchfornewchemotherapeutic agents. Dr.HenryrepliedtotheDSIRthattheresearchperformedbyBurroughsWellcome wasquitesatisfactory,andIamemphaticallyoftheopinionthatnosuccesscouldattend anycooperativeefforttoencourageandstimulatescientificresearchandthebestwayisto alloweachfirmtomaketheirownarrangement.HeemphasisedO'Briensearlier considerationthatwhatwasrequiredwasclosecollaborationbetweenchemistsand
34 physiologistsascouldalreadybeachievedatBurroughsWellcome. Thefirmremained
reluctanttosharetheirexpertisewithothers. However,BurroughsWellcomewerequicktosuggestthatifanyproductsarose fromtheDSIR,whichwerelikelytobeofindustrialinterest,thentheexperimental departmentwouldbekeentotakeupthework.HenrycommentedfurtherthattheDSIR planforcollaborativeresearch: doesnotstrikemeasfeasible,partlybecauseofthecomplicationsinvolved bythemedicalsideofthequestionandpartlybecauseofthecircumstances, objectsandoutlookofthecomponentpartsoftheindividualaretoovaried 35 incharactertopermitit. TheDSIRmadeaformalapproachtotheMRCtocollaboratetodevelopnew chemotherapeuticagents,butthesechemistryventureseventuallyfoundered,especiallyas theycouldonlyoffernonexclusivelicensesandbecausetheyreliedonexternal
36 laboratories.Asmoneybecameshort,jointcollaborationswereeventuallyabandoned.
34
T.A.HenrytoA.W.Crossley,(9July1925),WF:STCS/G/49(replytoletterof23 June1925).
35 36
T.A.HenrytoA.W.Crossley,(9July1925),WF:STCS/G/49.
320
BurroughsWellcomeStrategyintheInterwarPeriod.
321
SincethedepartureofCarrandhiscolleagues,BurroughsWellcomehadadopteda protectiveapproach,limitingstafffrom presentingdataandattendingexternalmeetingsfor fearofevenmorebeingpoached.Theinsularity,whichhadbeenthehallmarkof BurroughsWellcome,alreadyapparentintheirdealingswiththeMRC,begantobe questionedbySTCmembersinmid1926. Theeventwhichseemstohavetriggeredthisreappraisalseemstohavebeenthe inauguralpresidentialaddress:ThePositionandProspectsoftheOrganicChemical IndustryinthisCountrybyFrancisCarrtotheSocietyoftheChemicalIndustryatits ManchestermeetinginJuly1926.Hecalledforgreateremphasisonsyntheticdrugsrather thanthebiologicalsandthestandardpreparationsuponwhichBurroughsWellcomehad
37 chosentoconcentrate. JowettreferredtoFrancisCarr'snewpositionasPresidentofthe
H.A.D.JowetttoG.E.Pearson,Cooperation,STCMeeting,(24July1926), WF:STCS/G/49.
39
321
BurroughsWellcomeStrategyintheInterwarPeriod.
322
Thedebateaboutthefirmsrelationshipwithacademicsandclinicianswasevidently
40 difficulttoarrange,duetoPearsongoingaway. FortunatelythisledtobothO'Brienand 41 JowettsettingoutpositionpaperstoPearsononexternalrelations. Jowettdescribedhow
Jowetthadexperiencedrefusalsanddiscouragementregardingattendanceat externalmeetings,thoughhefeltthatafter30yearsatthefirmhismotivesforattending
40 41
R.A.O'BrientoG.E.Pearson,(28October1926),WF:STCS/G/49.
H.A.D.JowetttoG.E.Pearson,(12October1926):4,WF:STCS/G/49 MinutesofResearchConference,1.RawMaterialtoResearchers,(29October1926).
42
322
BurroughsWellcomeStrategyintheInterwarPeriod.
323
couldnotbequestioned.Hestatedthat:Ihaveonlytheinterestsofthefirmatheartand
46 donotinanywayseekpersonaladvancementor'kudos'outsidethefirm. Therewere
Asaconsequenceoftheirlackofinvolvementinexternalactivities,Jowettfeltthat BurroughsWellcomenolongeroccupiedaprivilegedpositioninBritain.Thesewere
46 47 48
H.A.D.JowetttoG.E.Pearson,(12October1926),WF:STCS/G/49. JocelynFieldThorpe,ObituaryJ.Chem.Soc.(1941):444.
323
BurroughsWellcomeStrategyintheInterwarPeriod.
324
50 yearsofconsolidation. BurroughsWellcomehadbeeninitiallycautiousintheir
assessmentofinsulinwhereasJowettstated:BritishDrugHousesstakedeverythingon it.Jowettrealisedthat:CarrandBDHarenowalwaysassociatedwithinsulin,and
51 BurroughsWellcomeandmyselfarewithoutrecognition. Heregrettedthatinregard
borocaine,hexylresorcinolandthyroxin,aswellasinsulin.Inordertoavoidlagging behindinthefuture,BurroughsWellcomehadtothinknotonlyofexploitingtheirown discoveries,butalsothosemadeexternally,andinordertoachievethisclosercontactwas requiredwithexternalestablishmentsandwithclinicians. Itwillberecalledalsothat1926sawmajorupheavalsintheindustrywiththe establishmentofIGFarbenandImperialChemicalIndustries.WhenBritishDrugHouses wasestablishedasapubliclimitedcompanyinFebruary1926,theyemployed30trained chemistsandaround40pharmacistswithapayrollofover1,200andanauthorisedcapital of642,000.Thefirmproduced1millionpillsperday,threequartersofatonof ointmentsandover1,000gallonsof3,500chemicalsmonthly. BurroughsWellcomehadnotcapitalisedonitsearlylinkswithgovernmentandits uniquepositionasthefirstholderofaHomeOfficelicensetoperformbiological standardisationtests.Increasingly,thestaffoftheMRCandthePharmaceuticalSociety tookacentralroleandyettheyhadallgainedtheirexperienceatBurroughsWellcome:
53 Dale,Laidlaw,HartleyandBurn. Jowettsconcernwasthat:
50
HenrySolomonWellcomeinD.J.Jeremyetal,DictionaryofBusinessBiography V(London:Butterworths,1986).
51
H.A.D.JowetttoG.E.Pearson,Memorandumre.ScientificSocieties(12 October1926),WF:BA/S/6/49.
52
53
Ibid.
324
BurroughsWellcomeStrategyintheInterwarPeriod.
325
54
H.A.D.JowetttoG.E.Pearson,Memorandumre.ScientificSocieties,(12 October1926):3.WF:BA/S/6/49.
55
STCMeeting,(29October1926).WF:STCS/G/49. STCMeeting,(29October1926),WF:STCS/G/49.
STCMeeting,(24May1937WF:STCS/G/49,MinutesofResearchConference,1. RawMaterialtoResearchers.
325
BurroughsWellcomeStrategyintheInterwarPeriod.
326
thatinGermany: Hundredsofchemistsandphysiologicalassistantsareemployedworking underthecentraldirectionofthepharmacologist.Avastorganisationis necessary,thecastislargeandresultscannotbeexpectedwithoutyearsof work.HundredsofcompoundsweresynthesisedbeforeSalvarsanwas discovered.IrecentlysawrecordsatFrankfurtshowingthatM(eister), Lucius,Brninghadsynthesisedandtestedover2,000separatesubstances upto1924.Iwastoldthatthepharmacologistessentiallyresponsibleforthe discoveryofBayer205hadworkedfor15yearsdirectingabandofseveral 60 hundredphysiologistsandchemistsbeforethisonesuccesswasachieved. [Thus]Thereisanaturaltemptationtoinvestigatecompoundsmadebyotherchemical firmsandtotrybysubstitutiontoimproveonthem.Probablyitwillbeimpossibletoavoid
61 this.Herecommendedsyntheticsbutnotasthemaincourse. InfactBurroughs
wasimportantthattheseguidelineswereadheredtowhenrequestscameintoprepare smallquantitiesofanunlistedremedysothatthefirmdidnotwastetimepursuing
59
R.A.O'BrientoG.E.Pearson.PharmacologicalActivitiesoftheFoundation,(16 January1925),WF:STCS/G/49.
60
Ibid.
61
R.A.O'BrientoG.E.Pearson,re.SyntheticChemistry,STCMeeting,(16January 1925),WF:STCS/G/49.
62
STCMeeting,(19May1925),WF:STCS/G/49.
326
BurroughsWellcomeStrategyintheInterwarPeriod.
327
63 unprofitablelines. JowettsuggestedthattheSTCshouldbeextendedtoinclude
membersoftheworks,thegeneralmanager,publicitydepartment,andrepresentativesof
64 thesalesdepartment. Hewrotethat:
7.4BurroughsWellcomeandVitamins:IndecisionandDecisions. DuringthenineteenthcenturymuchworkwasdoneinFranceandGermanyto identifytheessentialnutritionalelements:abalanceddietoffat,protein,carbohydrateand certainmineralswasrequired.Inpublicationsbetween1901and1912,GowlandHopkins showedthatadditionalmicroscopicamountsofaccessoryfoodfactorswererequiredand EdwardMellanby collaboratedwithhimtoshowthebenefitsofcertainfoodsinrickets. CasimirFunk,aPolishinvestigatorattheListerInstituteisolatedthecrystallinesubstance protectiveofneuritis(beriberi)andbelievingittobeanamine,coinedthetermvitamine.It wasonlyafterhiscolleagueJackDrummondrecognisedthattheseaccessoryfactorswere notaminesthatthetermwaschangedtovitaminin1920andDrummondproposednaming thevitaminsalphabetically.By1924DrummondwasatUCHandhedevelopedasteam distillationmethodtopreparevitaminAfromcodliveroil,andthefollowingyearheand Rosenheimdevelopedanassayofthevitamin,givingapurplecolourwitharsenic
67 hydrochloride.
63 64 65
66 67
327
BurroughsWellcomeStrategyintheInterwarPeriod.
328
analysedextracts,whileTrevanarrangedtrials,keepingsamplestoobservehowmuch
69 deterioratedonstorage. BurroughsWellcomerespondedpositivelytoarequestfora
WhenvitaminAwaspreparedtheywereleftwiththerestofthecodliveroil
71 startingmaterialandsoughtwaysofutilisingthis. BurroughsWellcomenotedthatGlaxo 72 addedvitaminstotheirmilkproducts. TheyanalysedsuppliesofOstelin,producedby
GlaxoforvitaminAandDcontent,sotheycouldchallengetheclaimsmadebyGlaxoand
73 gainacompetitiveadvantage. However,theBurroughsWellcomeextractsalsodidnot 74 containappreciableVitaminA. After1925whenMcCollumshowedthatvitaminD
deficiencywasthecauseofrickets,HarriettChickattheListerInstituteshowedthat
68
R.P.T.DavenportHines,andJudySlinn,Glaxo:AHistoryto1962(Cambridge: CambridgeUniversityPress,1992):6897.
73 74
STCMeeting,(21October1925),WF:STCS/G/49. STCMeetings,(2February1926),WF:STCS/G/49.
328
BurroughsWellcomeStrategyintheInterwarPeriod.
329
andmarkettwoconcentratedpreparations,RadiomaltandOscodalandmonthly
76 propagandawassenttotherepresentatives. Herringanddugongoilsweretestedas 77 alternativesourcesandfoundtobebetterthanthecodoilsusedforGlaxo'sOstelin.
BurroughsWellcomewiththeproductionofVitaminDastheytookuplicensestothe
79 Steenbockpatents. BritishDrugHouseswerecompetinginthisareaaswellandtheir
vitaminApreparationwasissuedasavoleumandtheirmaterialwassaidtobefreeof vitaminDasithadbeentestedbyCarrsnewcolorimetrictest,sothatthepreparationwill facilitateclinicalexaminationofthetherapeuticpropertiesofvitaminA.Onceagain BurroughsWellcomeweretwostepsbehind,butin1927thepreirradiationsubstancewas characterisedinGermanyasanalreadyknownproduct,ergosterol. Havingdecidedthatitwasdifficulttomakeconcentratedvitaminpreparations, BurroughsWellcomesoondoubtedthattheyhadmadethecorrectdecisiontheywere certainthatiftheydidnotmarketconcentrates,otherslessscrupulouswoulddoso,despite theirversionscontaininglittleinthewayofvitamins.JowettnotifiedO'BrienoftheBDH interestinaconcentratedpreparationcombiningbothvitaminsAandDnotingthat:there willprobablybearealdemand.TheyhadalsonotedRosenheim'sletterin Natureand
75 76 77
78 79
329
BurroughsWellcomeStrategyintheInterwarPeriod.
330
80 attemptedhisextractionofoilfromcowliver. Byearly1928,thedecisionshadbeen
Codliveroilwasadvertisedascontainingnotonlyvitamins,butalso9598%fat, providingnourishment,andasthefatwasmostlyunsaturated,itwasbetterabsorbed. Malt extractwassaidtoprotectagainstoxidationduringextractionandtheproductwas97.7% digestible.Representativesweretoldtomakenoreferencestothegeographicoriginofthe preparations,buttoemphasisethetransparency,lackofodourandtaste.VitaminA concentrateandvitaminD,madeartificiallybyirradiationwereaddedtoarangeof BurroughsWellcomeproductsandthevitamincontentwasguaranteed. Inordertoensurethedemandwasnotseasonal,thestrategywastoemphasisethe needinspringtocounterthelowsunlevels,insummertocounteroverexertion(vitaminB
83 fortifies),inautumntobuilduplevelsandinwintertoprovidetheequivalentofsunshine.
Jowettpreparedamemooutliningthescientificrationalebehindtheworkon
84 vitamins,whichwastobethebasisofasalescampaign. VitaminBwaspreparedfrom
80 81 82
STCMeeting,(11October1927),WF:STCS/G/49. STCMeeting,(8February1928),WF:STCS/G/49.
G.E.PearsontoC.M.Wenyon,(5November1926,20February1928),WF:STC S/G/49.
83
84
85
330
BurroughsWellcomeStrategyintheInterwarPeriod.
331
Despitetheexternalsupportfortheproducts,thereremainedafeelingwithin BurroughsWellcomethatvitaminconcentrateswerenotnecessarilybeneficial.VitaminC
86 didnotkeepandtherewasnoreasontoanticipatealargeclinicaldemand.
87 Neverthelesstheconceptofgivingvitaminsfordeficiencydiseaseswaswellestablished.
Theproblemwasthatthepreparationshadlimitedandvariablevitamincontent.Petershad providedamethodologytopreparevitaminB,butBurroughsWellcomefoundthistobe
88 inactive. Inordertoevaluatetheneedforapreparation,travelerswereaskedtofindthe 89 demandfrominstitutesofTropicalMedicineinIndia,AssamandMalay. VitaminB1was
7.5ClinicalTrialsArrangedbyBurroughsWellcome.
86
87
88 89
90
331
BurroughsWellcomeStrategyintheInterwarPeriod.
332
uponit.Wecollectinthecourseoftime,andbypainfullyslowdegreesclinicalevidenceof
93 thevalueofIodicin. Andyetwhenarepresentativewasaskedaboutalternativemeans
ofadministeringIodicinandwhetheritwasfoundsubsequentlyintheurine,afurtherstudy
94 wasarrangedwithCohen,asthereseemedtobenoalternativetrialists. Thebestchance
91
92
STCMeetings,(21October1925and29October1926),WF:STCS/G/49.
G.Ansell,Obituary,LordCohenofBirkenheadClin.Radiology (July1978)29(4): 370N.Poynter,LordCohenofBirkenhead(19001977)Med.Hist.22(1)(January 1978):901 J.AmericanMedicalAssoc.238(10October1977):1672 BritishMedical Journal (20August1977):525 Lancet(20August1977):4134TheLiverpoolof HygieneanditsPhysiciansMedHist.(16October1972):31020.
93
CY(arepresentative)toBurroughsWellcome,(15July1925),discussedatSTC meetingon23February1926,WF:STCS/G/49.
94 95
STCMeeting,(23February1926),WF:STCS/G/49.
332
BurroughsWellcomeStrategyintheInterwarPeriod.
333
activeprinciple,Oestrone,whichhehadisolated,hadfirstbeendescribedinGermanyin 1915. HealsodiscoveredthatotherLondonfirmshadalreadybegunworkingonthis problem.OBrientoldPearsonthatheintendedtovisitseveralmedicalconferencesin Londonwiththeaimofdiscussingovarianandparathyroidhormonepreparationsandthe newmethodsoftestingthem.WhenTrevanandJowettnextmetwithDodds,herequested hundredweightquantitiesofthehormonalpreparation,whichhethentestedforBurroughs Wellcomeinpatients.Howeverinthiscase,BurroughsWellcomewasslowindeveloping thepreparationwhentheyhadanofferofclinicaltrials. BurroughsWellcomemanagedtogetanalgesicsandantisepticstestedbyDr.E.A.
97 McMahanattheRoyalInfirmaryinEdinburgh. YetwhenTrevanarrangedastudyof
benzoylephedrineasalocalanaestheticatGuy'sHospital,hefailedtoreceiveasingle
98 report. Somesmallstudiesgaveresultsthatdidnotsupporttheintendeduseofnovel
medicines.HenryarrangedastudyofascaridoleinchildreninDarlingtonbutitwas
99 unsuccessfuldespitetheparentchenopodiumoil(oilofAmericanwormseed) beingused
successfullyinGermanyandtheUnitedStates,andappearingtoworkwellinanimal experimentsperformedbyDr.LaidlawatMillHill.Furtherstudiesindogswereplanned
100 byOBrienatBeckenhamtoresolvethisandthedatawaseventuallypublished. When
96 97 98
99
ChemistryandIndustry (29October1926):803.
333
BurroughsWellcomeStrategyintheInterwarPeriod.
334
SirAndrewBalfourleftBurroughsWellcomein1923tobecomeDirectoroftheLondon SchoolofHygieneandTropicalMedicinewhenitwasformallyestablishedthefollowing
103 year. In 1924themuchtraveledCharlesMorleyWenyonsucceededBalfourasDirector
101 102
STCMeeting,(27March1931),WF:STCS/G/49.
334
BurroughsWellcomeStrategyintheInterwarPeriod.
335
thatwassetupin1926betweentheMRCandColonialOffice,immediatelyfollowingthe
104 ImperialConference.
OneoftheconcernsoftheColonialOfficewasthereemergenceofGermanyasa forceinpharmaceuticals,andaspecialconcernwastheprogressmadebyGermanyin developingdrugsfortropicalinfectiousdiseases.Bayer205ortryparsamidewasaspecific therapyfortreatingtrypanosomalinfections.JustasBritainhadreliedonGermanyfor antiseptics,anaesthetics,painkillersandSalvarsaninthe1914,apotentialconcernwasthe reliancenowonGermanyforantimalarialsshouldsuchapoliticalsituationariseagain. WhentheSTCwasestablishedin1925therewerealreadysomeTropical Medicinesonclinicaltrial,mostlyoverseas.HenrypointedouttotheDSIRthat BurroughsWellcomewasalreadycollaboratingwiththeschoolsofTropicalMedicinein EnglandandIndia,withthemedicaldepartmentofBristolUniversity,andwithother
105 medicinalinstitutesinBritain,China,BrazilandFormosa. Theworkonantimalarial
treatingkalaazarwithStibosanwerecomparedagainstthoseofNeostam(stibamine
107 glucoside). BurroughsWellcomeremainedcautiouswhiletheystillregardedthedrug
104
T.A.HenrytoA.W.Crossley,(7July1925),WF:STCS/G/49.
STCMeetings,(13February1925,21October192525February192623March 1928)WF:STCS/G/49.
107
335
BurroughsWellcomeStrategyintheInterwarPeriod.
336
toasSb150/136wassenttothesameclinicinNatalandtotwofurthercentresinSouth
112 110 111 Africatotreatbilharzias. NeilHamiltonFairley testeditinschistosomiasis, and
113 Wenyondiscussedtheresultsofanimaltestswithafurtherstibonatederivative. Dr.G.
CarmichaelLowofUniversityCollegeHospital,Londonpublishedafavourableaccountof stibamineandasaresultBurroughsWellcomebeganadvertisingandmadestrenuous
114 effortstogetaproductoflowtoxicity.
Neostamwasdifficulttomanufacture,butJowettmadeenoughtosupplyDr.
115 EdwardHindleofthekalaazarcommittee. By1928thereweresufficientstocksto 116 advertisetheproduct. Still,therewereoccasionalunexpectedfailuresofabatchin 117 toxicitytests. Eventuallytheproblemsbecametoomuchanditwasdecidednotto
renewthepatentofNeostam.ThoughthereremainedademandfromIndiaandChina,
108
STCMeeting,(25May1934),WF:STCS/G/49.
336
BurroughsWellcomeStrategyintheInterwarPeriod.
337
salesweresmalldespitesomefavourableclinicalreports.Initsplacethefirmbegantotest
118 Brahmachari'sureastibamine andvonHeydensneostibosanfrom India,neitherofwhich
119 wereavailableinEurope.
Despiteitsproblems,TrevanwasstilltestingNeostamin1936whenheevaluated
120 itsstabilityinsolution. Itwasthentestedinanewform,forlightandtemperature 121 stabilityandsamplesweresenttoChinaforevaluation. Neostamformulatedwith
glucosewaslesstoxic,butthenBurroughsWellcomebecameawareofanewGerman
122 preparation,Bayer561thatthreatenedtocompete. Muchoftherenewedinterestin
Becausedrugsbaseduponantimonywereeffective,aDrMuiralsoevaluatedtwo
125 newdrugsbasedonmercuryforleprosyinCalcutta,India. Havingcompletedone
leprosystudy,MuiraskedBurroughsWellcomeforasupplyofDr.BlairBellslead
118
STCMeeting,(13May1938),WF:STCS/G/49. STCMeeting,(2February1926),WF:STCS/G/49.
125
337
BurroughsWellcomeStrategyintheInterwarPeriod.
338
foundawillingtrialistBurroughsWellcomewereclearlykeentouseMuirtothefull.The newbenzoylatedcocaineanaestheticderivativesandorganicmercurialsweretestedin
128 syphilis,tuberculosisandleprosy. AttheSTCmeetingon12July1935Henryraisedthe
questionoftestingmethyleneblueandalsovitaminproductsforleprosy. Drugsprovidedforuseintropicalclimatesweretestedforstabilityatahigher
129 temperature,aswhenTrevansentephedrinetoIndiaandBaghdad. Trevanalsotested
medicine,BurroughsWellcomecircumventedmanyoftheproblemsofhavingdrugstested clinicallyinBritain. ThefirmshowedparticularinterestinantimalarialsfollowingthesuccessthatBayer hadwithAtebrin(mepacrine)discoveredin1930.Previouslytherehadbeenlimited successwithantimalarials,theonlysyntheticstoshowpromisebeingmethyleneblueand arsphenamine,neitherofwhichwereasactiveasnaturalquinine.WilliamRoehlofBayer developedtechniquesfortestingpotentialdrugsincanariesandininsanepatients. Promisingleadswerechemicallymodifieduntilaftertestingseveralhundredcompounds, plasmoquinewastestedclinicallyandmarketed,whenitwasshownthatitactedina differentwaytoquinineandimprovedtheefficacyofthelatterwhengivenin
126
127 128
129
130
338
BurroughsWellcomeStrategyintheInterwarPeriod.
339
whohadfirsttestedharmineandharmalineandfoundthemuselesshethenevaluated
134 hydroquinine.
Kingperformedteststoestablishchemicallywhyquinineandothercinchonaalkaloidswere
W.Sneader,(1985):26875. STCMeeting,(14Feb1934),WF:STCS/G/49.
MarkW.Weatherall,Gentlemen,Scientists,andDoctors:MedicineatCambridge 18001940(Cambridge:BoydellPress,2000).
134
135
STCMeeting,(28March1930),WF:STCS/G/49. STCMeeting,(19May1934),WF:STCS/G/49.
339
BurroughsWellcomeStrategyintheInterwarPeriod.
340
IodoBismutideofquininewasconsideredforAustraliawheredemandforbismuth metalpreparationswasdecreasing.Thisnewproductcouldbegivenlongtermwithout
138 stomatitisandtheWassermanntestwasnegativeearlier. HenryaskedTrevanfor
Itshouldbeclearfromthepreviousaccountthatfromtheendoftheinsulinwork untiltheoutbreakoftheSecondWar,BurroughsWellcomehadawiderangeofproducts indevelopment.TheSTCcontinuedtodebatewhethertoremainaUniversalprovider, orwhethertoconcentrateonsynthetics,biologicals,vitaminsortropicalmedicine. Probablythescaleoftheirdevelopmentworkhasbeenpreviouslyunderestimated becausemanyoftheirdrugswereaimedattropicalmedicine,orwerehormonalorvitamin preparationsthathavesincebeenreplaced.Ihavetriedtoshowhowtheclinicians,Trevan andWenyontookaleadroleinestablishingclinicaltests,thoughwithlimitedsuccessinthe UKuntiltheTTCwasestablished.CollaborationswiththeChemotherapyCommitteewere moresuccessfulbutprimarilyregardingoverseasstudiesintropicaldiseases.
136 137
SirCharlesHarrington,HaroldKing(1956):161.
STCMeeting,(28May1936),WF:STCS/G/49. STCMeeting,(19November1937),WF:STCS/G/49.
340
BurroughsWellcomeStrategyintheInterwarPeriod.
341
BurroughsWellcomecontinuedtoreleaseastreamofnewproductsfromthe establishmentoftheSTCuntiltheoutbreakofWorldWarTwo.Atotalof62separate productlaunchestookplaceintheperiod1925to1939thoughfewofthesewere synthetics.Theseincludedvariousformulationsofinsulin,hormoneextracts,purified vitamins,andinorganicpreparations,togetherwithpurifiedalkaloids Atthestartof1937therewasanimportantrequesttoBurroughsWellcomefrom theWarOfficeforalistofpossibleBritishsubstitutesforforeignsyntheticdrugs.The Governmenthadclearlylearnedalessonfromtheproblemsfacedattheoutbreakofthe FirstWorldWarandweremakingearlypreparationsincaseoffurtherhostilities. BurroughsWellcomereviewedthelistattheSTCof22January1937andbrokethelist
140 intoclassesofdrugsandtheequivalentthatBurroughsWellcomecouldoffer.
ThegovernmentwasinterestedinanalepticsofwhichBurroughsWellcomecould supplyCoramineandIcoralLocalanaesthetics(Percaine):Pyelographicsubstances(Per abrodiHypnotics(EvipanNa,Avertin,PentothalNa)Antimalarials(Atebrinand Plasmoquine).Researchwasongoingfornewanaleptics,hypnoticsandantimalarials thoughitwasnotpossibletosaythattheycouldpreparecommerciallypracticable substitutes.Theycommentedthat:alldrugsinthelistarepatentedandmanufacturewould nodoubtbetakenupiflicensestomanufacturecouldbesecuredbynegotiation,withthe patenteesorifpatenteeswerecompelledbyappropriatelegislationtograntlicenses.Sucha procedurewouldprobablybetooslowtobeuseful.Theymadeitclearhoweverthatitwas mostdesirablethatintheeventofWar,manufacturersshouldhavehadexperienceinthe productionofessentialdrugs,whichareatpresentimported.ItseemedclearthattheWar OfficewouldprefertodealwithasingleorganisationinthismatterandtheCommittee (STC)areoftheopinionthatMessrs.B.Wellcome&Co.mightsuggestthattheWar OfficeshouldprovideatonceashadowfactoryatDartfordwithasmallstaffofchemists toworkoutalltheprocessesforthemanufacture.BurroughsWellcomefurthersuggested thatifthiswasnotacceptable,theNationalChemicalLaboratoryatTeddingtonengagedin longtermresearch,wasthereforetechnicallycapableandcouldbeplacedatthedisposalof manufacturersthroughtheABCM.Thiswasadevelopmentofaprocedurealreadyputin operationforanentirelynewdrugrecentlydiscovered.Eitherwouldbequickerthanathird
140
STCMeeting,(22January1937),WF:STCS/G/49.
341
BurroughsWellcomeStrategyintheInterwarPeriod.
342
AttheSTCof29September1939,theSTCconsideredthelistof40Germandrugs
142 anddecidedwhichtoconcentrateonwithaviewtomanufactureoverthenext3months. 143 Therewerealsosomethatwerenotconsideredworthmanufacturing.
theleaduptotheWarandcollaboratedwithHoffmanlaRocheandSandoz,andwith
141
C.M.WenyontoAMD3,WarOffice,STCMeeting,(9February1937),WF:STC S/G/49.
142
Adalin(carbromaliumBP),ascorbicacid,Butolan,Icoral,Lopion,Moogroliodinised, Oestrodiol,Oestrone,Pentothal(Abbott),Perabrodil,Rivanol,Surfen,Zephiran,ibid.
144
342
BurroughsWellcomeStrategyintheInterwarPeriod.
343
theWPRLsucceedingR.A.OBrien,andA.C.Whitetookoverhisroleasheadofthe
148 pharmacologydepartment.
DalelaterwrotetoElliott:Thereisstillmuchtobedonetomakegoodthelong yearsofneglectbyWellcomeandbywhomheappointedandleftinchargeandtocatchup
149 withmissedopportunities. ProfessorElliottthoughtthecompanyoughttobe
emphasisingresearch.In1938hewrote:specialmenandespecially(Sir)Andrew BalfourwerealwayseagertokeepthemselvesandtheirBureau(ofScientificResearch)
145
G.H.Lyall,H.H.Dale,L.C.Bullock,M.Prince,T.R.Elliott,TheWilloftheLate SirHenryWellcomeTheLancet(1937):289.
146
J.H.Gaddum,JohnWilliamTrevan(1957):275.
H.H.DaletoT.R.Elliott,(10December1957),inH.DaleArchivesattheRoyal SocietyMemoirs,HD36/4.26.
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dissociatedinthepubliceyefromthecommercialsideThesewereundistinguished
150 years. Howeveritwasnotallbleakandsomeprogresswasmade.Ihavedemonstrated
thesignificanteffortsthatwentintodevelopingsyntheticdrugs.BurroughsWellcomes approachcouldbeclassedasafastfollower.Theykeptaclosewatchonthemedical literatureandsoughtfeedbackfromthemedicalprofessionandimproveduponGerman drugs,particularlyifavalidpatentwasnotinplace.Thedrugsproducedweremoreactive, moresoluble,withlesssideeffectsorwereeasiertoadminister.Themodifieddrugswere patentedwherepossible,themanufactureofsomeweresimplycopiedandproducedunder license.Theadvancesintheirchemicalunderstandingtoachievethisshouldnotbe underestimated,butBurroughsWellcomeneverthreatenedtoestablishempiricresearchon theGermanscale.Bypreparingaseriesofsimilardrugs,observationsweremadeon structurefunctionactivities.Clinicaltrialswereestablished,thoughitwasmoredifficultin theBritainthaninthetropics,andmanyadvanceswereaimedatTropicalMedicine,always aninterestofWellcomeandWenyon,andofincreasingstrategicimportanceastheSecond WorldWarthreatened.Bytheendofthisperiodchemicallaboratoryfacilitieshad expandedsignificantlyandsotohadthemanufacturingcapacityoffirmssuchasBurroughs Wellcome,Boots,Glaxo,Allen&HanburysandBritishDrugHouses.
150
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CHAPTEREIGHT:TheTherapeuticTrialsCommitteeoftheMRC. 8.1Introduction. InpreviouschaptersIhaveshownthatasignificantproblemfortheBritish pharmaceuticalfirmshadinhavingtheirnoveldrugstestedclinically.Chapter6emphasised repeatedABCMcampaignstotheMRCfrom1922to1930forameansofperforming clinicaltrialsofpharmaceuticalfirmsdrugs,whiletheMRCtestedinsulinandotherdrugs fromabroad.TheMRCtesteddrugsduringtheGreatWar(chapter4)andthen coordinatedbiologicalstandardisationofdrugs(chapter5).Chapter7exemplifiedthe difficultiesthatBurroughsWellcomeencounteredinhavingnewdrugstestedinBritain, mostoftheirsuccessfulclinicalstudiesbeingintropicalmedicinecentresoverseas. TheMRChaddifficultiesincollatingclinicalresponsestoSalvarsan,duetothe variabilityofthedrugsupplied,andthecircumstancesofwartimerecordkeeping.Inthe secondSalvarsanCommitteefrom1918,theMRCclearlydefendedBritishpreparationsin comparisonwithGermancompetitors,toensureBritishproductionofSalvarsan.Itwasthe samewithinsulin,excludingcompetitivethreatsfromEliLillyofAmericaandLeoof Denmark.StimulationoftheBritishethicalpharmaceuticalindustrywenthandinhand withtheMRCaimofregulatingdrugqualityandevolvingasystemofclinicalresearchin Britain.Theyweremorecomfortablewhenadrugsuchasinsulinwasstandardisedand evaluatedinthelaboratory,andglucoselevelsweremeasuredasasignalofefficacyin clinicalstudiesintheirownresearchcentres. Liebenauarguedthatthedevelopmentofinsulinwassymbolicofthechanging industrygovernmentrelationsandpartofanMRCaimtoregulatetheBritish
1 pharmaceuticalindustry. Valieralsoreferredtothisassymbolicofthechanging
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testedsotheycouldcommercialisethem. Britishcompaniesclearlyhaddifficultyinarrangingclinicaltrialsoftheirown products,aspreviouslyhighlightedbyGeorgePearsonofBurroughsWellcomein1922. TheestablishmentoftheMRCChemotherapyCommitteein1927didnothelpthe pharmaceuticalfirmsasitfocusedoncollaborationwiththeDSIRandontropical medicines,whichwereamongthefewdrugsthatBurroughsWellcomemanagedtoget testedinthecoloniesasdescribedinchapter7.4 Inthe1920s,Britishfirmsthatcouldnot gettheirnewproductsclinicallytested,dependedonwhateveraffidavitstheycouldget. Thefollowingexampleoftrichlorophenylmethyliodosalicyl(morewidelyknownasthe antisepticT.C.P)fromBritishAlkaloidsLimitedwastypical: Thepreparationistestifiedtobymanymembersofthemedicalprofession asbeingnontoxicandanalgesicandausefulapplicationasagargleorspray inaffectionsofthenoseorthroatandasalotioninwoundsandscaldsas 5 wellasineczema,chilblainsandhaemorrhoids. Thisabovecaseishowever,unusual,asthedrugsucceededduetoadvertisingtothe public,whereasadrugmarketedtophysicianswouldhavefailedwithoutsupporting publications.
3 4
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Pharmacopoeia,companyhistoriesandprimarysourcesatBurroughsWellcome, particularlytheScientific&TechnicalCommittee(STC)minutes.Asynthesisofthese diversesourcesallowedmetofollowtheprogressofmostdrugsexamined,bothfromthe TTCperspectiveandthatofthecompanyprovidingthedrug,andtherebygivinganinsight intothestateofBritishdrugdevelopment,whereaspreviousresearchhasfocussedonlyon themajordrugs. Thischapterexaminesthetypesofcompoundsputforward,andassesseswhich BritishandforeignfirmsweremostactiveinprovidingdrugsfortheTTC.Itgivesan insightintohowtheTTCselecteddrugsforclinicaltrialandhowtheyorganisedthetrials. Threethemesemerge,thedifferingemphasisplacedonsyntheticchemistrybetweenfirms thecontinuityoftestingwithingiventherapeuticfields,bothintermsoftheclinical investigatorsandtheevaluationsperformedandthefailureofahighproportionofthe TTCstudies.TheexampleoforganotherapyshowshowtheTTCpursuedtheMRC interestinthistherapeuticapproach,whichinitiallyreliedonbiologicalstandardisationof thedrugs,butsubsequentlyextractswerereplacedbysyntheticversions.Notablealsowas thechangearound1935,asaresultoftheBayersdiscoveryofProntosil,whenthe realisationthattheactiveingredientwasnotpatentprotectedledtomorefirmsadopting syntheticdrugsandalsototheirincreasedacceptancebyphysicians,keentoobtainsamples ofthesepowerfulnewtherapies. ThepressurefromtheABCMfortheproposedTherapeuticTrialsCommitteepaid off in1931atatimeofincreasingGovernmentreceptivenesstotheneedtoexclude ineffectivemedicines,andtogiveprecedencetothescientificallyvalidateddrugsofethical
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7 pharmaceuticalmanufacturers. Attemptstocontroloftheclaimsmadebymanufacturers,
thepricingofdrugs,andespeciallyimports,wasalsobeforeParliament,andthePharmacy andPoisonsBill(concerninglicensingofpharmacists)wasinthecommitteestageinthe
10 Lords,havingbeenintroducedon17December1930.
TheTTCwasalsoestablishedduringaperiodofpoortradebalances, unemployment,increasednationalismandthreatsoftariffs.By19September1931foreign
11 creditswereexhaustedandthegoldstandardwasabandoned. Inthemidstofthe
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consideredthatitwasthemostdifficultperiodeverfaced,withatradedeficitof9m.He calledforfurtherprotectionforfinechemicals,asgivenbytheDyestuffsActforthe23
12 millionofdyesimportedintotheEmpire. ThePureFoodCouncil,BritishMedical
Association,PharmaceuticalSocietyandProprietaryMedicinesManufacturersmetto
13 discusstheneedforaregistryofproprietarydrugs,medicines,andmethodsoftreatment.
However,inthegrowingeconomicgloom,thepossibilityofenforcedregulationofdrugs wasdroppedtoallowthewholesessionofParliamenttobedevotedtotheNational
14 EconomyBill. Thus,thecollaborationofrepresentativesoftheindustryandtheMRC
waspartofmuchbroaderencouragementoftheinfantBritishIndustryandmorefollowed
15 suchastheImportDutiesBillintroducedbyChamberlaininFebruary1932.
Incontrasttoincreasinggovernmentinfluenceontheclaims,strengthandvariability ofmedicines,someinfluentialclinicianssuchasLordDawson,PresidentoftheRoyal CollegeofPhysicians,stronglyadvocatedthatWhitehallshouldplaynopartindrug regulations,leavingdoctorstoprescribe,astheywanted.ThequarrelsthatLordDawson andLordMoynihan,PresidentsoftheRoyalCollegeofPhysiciansandofSurgeons respectively,hadwiththeMRCweredocumentedpreviously.Moynihandidnotthink MRCresearchershadenoughclinicaljudgmentskills.However,FletcherattheMRC insistedthattheTTCdidnotaimtotelldoctorswhichtherapiestouse,onlytotestnovel drugstoseeiftheyhadclinicalutilityandthattheyweresafetoprescribe.Whetherthey werethenprescribedwasamatterforthedoctorsthemselvesandthefirmspromotingthe
11
TheDyestuffsActChemist&Druggist113.2(18October1930):475ABCM: DyesandTextiles(18October1930):486 A.J.P.Taylor,EnglishHistory19141945 (Oxford:ClarendonPress,1988):28397. 12 J.DavidsonPratt,Chemist&Druggist114.2(31October1931):551 Chemist& Druggist 114.2(26December1931):757.ThegrowthinChemicalindustriessincethe WarwasintheratioU.S.6.3,Germany5.2,andFrance4.8comparedwithBritain2.1and worldtraderosefrom11.5min1913to23min1928L.F.Haber,TheChemical Industry19001930:InternationalGrowthandTechnologicalChange(Oxford: ClarendonPress,1971):1,7.
13
ABCM:BritishChemicals:theirManufacturersandUses(London:ABCM,1927, 1929,1931).
14
15
A.J.P.Taylor,(1988):32150. A.J.P.Taylor,(1988):330.
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collaboratedwithbothDaleandElliottonacommitteearrangingtrialsinpernicious
18 anaemia.Fraserwasanexpertinthestructureactivityrelationshipsofalkaloids. He
wasamemberofthePharmacopoeiaCommissionfrom1928,remainingamemberuntil
19 October1944. FrankH.K.Green,previouslyarecipientofanMRCgrantforresearchat
St.BartholomewshadbeenamemberoftheMRCsince1929.Hewouldhavebeena
20 consultantbutforhisbronchiticasthma,soadeskjobasSecretaryoftheTTCwasideal.
16
IreviewedthefilesattheMRCbuildingsjustbeforethemovetothePROandata timewhenmanyfileswerebeingshredded. 17 Retrospecton40yearsofPractice:BMAPresidentialAddress,BritishMedical Journal (29July1939):209. 18 MRCMinutesII,(16July1920):114MRCMinutesII,(15July1927):156. 19 BritishPharmacopoeia (London:GeneralMedicalCouncil,1948):viii ix. 20 MaisieFletcher,TheBrightCountenance:aPersonalBiographyofWalterMorley Fletcher(Hodder&Stoughton,1957):323F.H.K.Green,ClinicalEvaluationof RemediesinBritain,Brit.Med.Bulletin 2(1944):5860. 21 JoanAustokerandLindaBryder(eds.),(1989):76,214,224M.W.Weatherall, Gentlemen,ScientistsandDoctors:MedicineatCambridge18001940(Cambridge: BoydellPress,2000):2778.
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StreetfigureandaseniorurologistatKingsCollegeandsurgeonatSt.PetersHospital,
22 London. SirEdwardFarquharBuzzard,aneurologistandsuccessortoWilliamOsleras
inLondonandhadhelpedtofoundtheBritish(laterRoyal)CollegeofObstetriciansand
26 Gynaecologistsin1929,andin1930hewasPresidentoftheRoyalSociety.
22
TrotterwasapupilofSirVictorHorsley.HewasasurgeonatUCHfromitsopening in1906:W.R.Merrington,UCHanditsMedicalSchool (London:Heinemann,1976): 47,102:MRCFile1523/1J.H.Gaddum,WilfredBattenLewisTrotter.Biographical MemoirsofFellowsoftheRoyalSociety 3(1957):27388. 24 FromJanuary1934FredMenzies,MedicalOfficerofHealth,LondonCounty Council,andDr.ThomasCarnwath,aseniormedicalofficerintheMinistryofHealthwere added.LindaBryder,PublicHealthResearchandtheMRCinJoanAustokerandLinda Bryder(eds.),(1989):5982FromJune1934,ProfessorA.J.Clarkwasadded:D.H. Clark,AlfredJosephClark18851941,aMemoir(Glastonbury:C.&J.Clark,1985) MRCMinutesII,(29October1931):128HelenK.Valier,(UniversityofManchester: PhDthesis,2002). 25 SirHenryDale,EdwardMellanby.ObituaryNoticesofFellowsoftheRoyalSociety 1(1955):193222. 26 ObituaryofThomasWattsEden(8May186422September1946BritishMedical Journal (5October1946):517. 27 TheTherapeuticTrialsCommittee.FacilitiesfortheClinicalTestingofNew Remedies,(6March1931),MRCFile1523/1(TTC).
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OneweeklateralongarticleappearedintheBritishMedicalJournalreinforcingnotonly thefunctionsbutalsotheneedforthenewlyconstitutedcommittee. AsignofthetimesisthesettingupoftheTherapeuticTrialsCommittee. Untilnowithasbeenlefttothemanufacturerstoarrangeastheythoughtfit forclinicaltrials,withtheattendantdifficultyofnotalwaysbeingableto ensurethenecessarytestsbeingconductedinasufficientnumberofcases.As aruleIbelieveitisthecustomforfreesamplestobesuppliedtosuchprivate practitionersasarewillingtoacceptthem,andtorelyuponthose practitionerstomakeuseofthemincasesthoughttobesuitable.Butwhat happensIimagineisthatinmanyinstancesthesamplesareonlytriedbyway ofexperiment,whentheordinaryremedieshavefailedinparticularcases. Evidenceofthissortofthingcanbefurnishedbymanychemistswhocarry onbusinessindistrictswheredoctorsfondoftryingnewproductsallegedto possessremedialpropertiesareinpractice.Sometimesgoodluck attendstheempiricaltrials,butmorefrequentlyitdoesnot,andanelementof uncertaintyseemstoattachitselftotheresultsobtainedbysuchhappygo luckyclinicaltrialssocalled.Moresystematicmethodsdoubtless characterisetheprocedureadoptedbysomemanufacturersofnewproducts offeredforthetreatmentofdisease,butitseemsalltothegoodthat opportunityshouldnowbeprovidedforarrangingproperlycontrolled clinicaltests.Thenewcommitteeisastrongone,includingindividualsofthe highestreputesandbothmedicineandpharmacyoughttobenefitbyits 31 existence. ThisdefinitionoftheTTCwasbroaderthanthatinterpretedbyValierwhowrotethatit
32 wassetuptoensurethatpotentiallyuseful syntheticproductswerequicklyrecognised.
28 29 30 31 32
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receivedarequestfromtheGermanfirm,Scheringforhelpinarrangingtestsofanewdrug
34 called'SolganolB'oraurothioglucose,agoldbaseddrug.
ScheringhadindependentlyapproachedaDr.WilliamRobertsonSnodgrassat GlasgowRoyalInfirmary,whoagreedtotreat30casesforthem.Onhearingofthis,the
36 ProfessorofBacteriology,C.H.Browning attheUniversityofGlasgowsuggestedthat
SnodgrassmightbeinvitedtosubmithisrequestinsteadtotheTTC,butsecretaryF.H.K.
37 Green considered:itwashardlyfairtotheABCMthatthefirstactivityofthenew 38 committeeshouldbetheacceptanceofareportontheGermandrug. Dalecommented:
33
F.H.K.GreentoC.H.Browning,(3March1931)MRCFile1523/1(TTC).
F.H.K.GreentoH.H.Dale,(3March1931),ThomasRentonElliottFiles, TherapeuticTrialsCommittee(TTC)193343,WellcomeInstitute,WI:GC/42,13/1.
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itwasofcourseverystupidofBrowningtobringthatsuggestiontousviathefirmin
39 question.
suchasbytheResearchAssociationofBritishRubberManufacturersinMalaya,tohave Querbrachitoltested,whenintheabsenceofdataItoccurredthatthisproductmight
41 possesssomepropertiesofuseitwasrejected.
Ellissuggestedthatinordertoavoidfuturecontroversy,studiesshouldbe performedatmorethanonecentrethosewheretheMRCalreadyfundedworkandwhere
42 theyhadtrainedstaffinplace. TheTTCinsistedthatthemanufacturingfirmprovidedall
H.H.DaletoF.H.K.Green,(27February1931),MRCFile1523/1(TTC). FirstmeetingoftheTTC,(8July1931),MRCFile1523/15(TTC).
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BritishDrugHouses,submittedtheirOestrinpreparationandfollowedwiththreedrugsfor
46 thenextmeetingoftheTTCinJanuary1932.
BritishPharmacopoeiaof1948,soitappearsnottohavebeendeveloped.Ofthedrugs offeredtotheCommittee,itappearsthattheygaveprioritytothosethatcouldbeassayed
43
TheTTCexamined59remediesbetween19319TTCMinutes110,MRCFile 1523/15.Furthercompoundswereforwardedbutnotdiscussedatthemainmeetings.
44
F.H.K.GreentoT.R.Elliott(25June1934)T.R.ElliotttoF.H.K.Green(27June 1934),T.R.ElliottFilesTTC193334WIGC/42.
45 46 47
TTCMinutes1,(8July1931),MRCFile1523/15. TTCMinutes2,(15January1932),MRCFile1523/15.
NeitherofthesedrugsappearsintheBritishPharmacopoeiaof1948andtheywere presumablynotmarketed.(London:BritishPharmacopoeia,1948).
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AmericanpharmaceuticalfirmssuchasArmouradvertisedanextensiverangeof
51 organotherapiesin1918. Areportin1919hadindicatedthepotentialroleofpituitary 52 extractsfortreatingmenstrualmigraines,andyetpreparationswereofvariablestrength.
M.Borrell,OrganotherapyandtheEmergenceofReproductiveEndocrinologyJ. Hist.Biol.(1985)18:130M.Borrell,Organotherapy,BritishPhysiology,andDiscovery oftheInternalSecretionsJ.Hist.Biol.(1976)9:23568 BritishMedicalJournal (6 February,1915):243247E.C.Dodds,TheHormonesandtheirChemicalRelations Lancet(19May1934):104854SirHumphreyRolleston,TheHistoryof OrganotherapyBritishMedicalJournal (15May1937):103336SirW.LangdonBrown, RecentAdvancesinOrganotherapyPharmaceuticalJournal 141(30July1938):93. 49 W.Sneader,(1985):192. 50 C.Harrington,G.Barger,ChemistryofThyroxine.(III)ConstitutionandSynthesis ofThyroxineBiochemicalJournal 21(1927):169. 51 Thesubstancesandglandpreparationsincludedbronchial,cardin,cerebrenin,corpus luteum,duodenal,lymphatic,mammary,orchitic,ovarian,pancreas,parotidandpineal Chemist&Druggist(6July1918)suppl.V.
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53 MRC. Eachnewhormonewasexaminedinasimilarfashion.Firstlyextractsweremade
WalterM.FletchersetupaSexHormonesCommitteewithintheChemotherapy
55 Committeein1930,includingDale,WattsEdenandEllis. Organotherapywaswithinthe
comfortzoneoftheMRC,becausetheorganextractshadtoundergobiological standardisationintheirlaboratories.HaroldKingattheNIMRinvestigatedthechemical
56 structureofthehormones,justasGeorgeBargerhadwiththyroxinein1927. Because
HormoneswasestablishedunderAlanParkes(laterSirAlan),whohadpreviously
58 collaboratedwithGuyMarrianatUCH andalsowithProfessorE.C.(LaterSirCharles) 59 Doddsonhormones.
52 53
JoanAustoker,LindaBryderin JoanAustokerandLindaBryder(eds.),(1989):489.
DoddswasProfoftheUniversityofLondon:MRCMinutesII,(30April1926):74: E.C.Dodds,SyntheticOestrogensEndeavour(1947):1457E.C.Dodds,L.
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BurroughsWellcometookanearlyinterestinorganotherapyandwas,likemany firmsinvolvedintheinsulinstudies.Theyhadalreadyplacedtheirthyroxinepreparationon
60 themarketinSeptember1926. BurroughsWellcomesanteriorpituitarylobepreparation,
neoInfundin,wasmarketedin1931andwasclaimedtobefreefromthepressorprinciples
61 associatedwithearlierextracts. ThefirsthormonesubmittedtotheTTCbyBurroughs
supportedDoisy,andheisolatedthecrystallinehormonein1924.TheMRChadsupported ovarianhormoneresearchsincetheearly1920s,culminatinginthedetectionofovarian
Goldberg,W.Lawson,R.Robinson,OestrogenicActivityofCertainSynthetic CompoundsNature(1938)141:247.
60 61
406.
62 63 64
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66 hormonesintheurineofpregnantwomenbyGuyMarrianatUniversityCollegeHospital.
AmericanfirmofParkeDavisandtheGermanfirm,Scheringcommerciallyproduced
69 oestroneandrelatedhormones. Oestrinwasshowntohelp23outof25womenwith 70 menstrualmigraineinanindependentclinicalstudyin1932. Dr.JohnChassarMoir,who
TheMRCSexHormonescommitteerecommendedtotheTTCthatstandards shouldbedefinedandthatclinicaltrialsbearrangedforOestrinandforsomeBritishfirm
66
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72 toundertakeitsproductionandBDHsubmittedtheirversion. Doddsreported
favourableclinicaloutcomesinhisstudies,whichencouragedhimtoattemptthe
73 identificationandsynthesisofOestrin. Inthesummerof1932,theMRCcollaborated
withtheLeagueofNationstoestablishInternationalStandardsUnitsforoestrogenic hormonesandAlanParkesdepartmentperformedmanystudiesofsexhormones
74 preventingfertility. Withabiologicaltestinplacetomeasuretheoverallactivity,therace 75 begantodefinetheactivesubstancewithintheextracts.
Havingfollowedthedevelopmentofthyroxine,BurroughsWellcomedecidedto
76 keepawatchonthepossibilitiesofsyntheticoestrogeniccompoundsofthistype. In
givenorallywasasuccessfulproductforBurroughsWellcomeandotherfirms,butthey
78 alsoprovidedDoddswithlargequantitiesofmaterialtotrytosynthesiseit.
MRCMinutesIII,(13March1931):39. E.C.Dodds,F.Dickens,S.Wright,ObservationsuponthePreparationofthe OvarianHormoneBiochemicalJournal 19(1925):85359E.C.Dodds,J.D.Robertson, ClinicalExperimentswithOestrinLancet I(1930):13902. 74 J.Austoker,L.Bryder,in JoanAustokerandLindaBryder(eds.),(1989):49. 75 Oestrinisstillusedinitsmodernformasoestrogen,R.E.Jowett,SomeUnusual ExperienceswithOestrinTherapyJ.Laryngol.Otol.82(1)(1968):6971. 76 STCMeeting,(19May1933),WF:STCS/G/49. 77 STCMeeting,(14December1934),WF:STCS/G/49MRCMinutesII,(26June 1931):91.
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syntheticsubstitutesstilboestrol,hexoestrolanddienoestrol,werepreparedinJanuary
79 1938.
78 79
R.A.OBrientoH.A.D.Jowett,(26May1925),WF:STCS/G/49. S.A.B.Kipping,ChemistryandIndustry (25February1963):304W.Sneader, (1985):196,201,336,340LordTodd,J.W.Cornforth,RobertRobinsonBiographical MemoirsofFellowsoftheRoyalSociety 22(1976)415527STCMeeting,(31January 1939),WF:STCS/G/49E.C.Dodds,W.Lawson,ASimpleAromaticAgentwithan ActivityofthesameOrderasthatofOestroneNature139(1937):627E.C.Dodds,L. Goldberg,W.Lawson,R.Robinson,OestrogenicActivityofCertainSynthetic CompoundsNature141(1938):24748. 80 TTCMinute9,(14July1938),MRCFile1523/15W.R.Winterton,T.N. MacGregor,ClinicalObservationswithStilboestrol(Diethylstilboestrol)BritishMedical Journal (7January1939):1012ANewSyntheticOestrogenBritishMedicalJournal (7 January1939)2334AlfredA.Loewer,TherapeuticTrialsofDiethylstilboestrolBritish MedicalJournal (7January1939):13. 81 P.M.F.Bishop,M.Boycott,S.Zuckermann,TheOestrogenicPropertiesof Stilboestrol(diethylstilboestrol)Lancet(7January1939):5P.M.F.Bishop,R.K. Bowes,M.Boycott,R.Kellar,T.N.MacGregor,B.C.Markers,OestrogenicProperties ofStilboestroldiproprionateandHexoestrolLancet(6April1940):629633Synthetic oestrogensBritishMedicalJournal (25February1939):351.
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extracts,promisedearlysuccessanditwasnotlongbeforeBoots,BDHandOxojoined
82 BurroughsWellcomeinmanufacturingstilboestrolampoulesandtablets.
OrganonofOssinHollandapproachedtheTTCtoperformthefirstUKtrialsofsuprarenal corticalextractonpatientswithAddisonsdisease,adeficiencydiseasefirstdescribedby
84 ThomasAddisonin1855. TheTTCwereconcernedthatsuprarenalcorticalextracts
calledEucortone(Allen&Hanburys)andEschatin(ParkeDavis)werealreadyonthe
85 marketandbothwereexpensive. Organonsversionwasanunpatentedpreparationwith
82
SexHormones:StandardisedCommercialPreparations,PharmaceuticalJournal 142 (27April1939)436442. 83 W.Sneader,(1985):221. 84 th SirJohnConybeare(ed.),ATextbookofMedicine(Edinburgh,E.S.Livingstone,9 edition1949):2578. 85 T.R.ElliottFile,WIGC/42Eucortone,Corton(A&H):extractofadrenalcortexfor thetreatmentofAddisonsdiseaseandotherconditionshighlyactive,highlypurified (London:Allen&Hanburys,1938)advertisementatWellcomeInstituteQV26 1938A42e. 86 TTCMinutes5,(5March1934),MRCFile1523/15. 87 F.H.K.GreentoT.R.Elliott,(20December1933),T.R.ElliottFiles,WIGC/42 TTC193334TTCMinutes5,(5March1934),MRCFile1523/15.
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thenleavehimtoslideback.Yetthehospitalmightnotrelishthisaftermathof 88 theinvestigation.
InFebruary1934aconferencewasheldtodiscusstheclinicaltrialsofsuprarenalcortex extractsandtheCommitteedecidedtodowhattheMRCdidbest,toperformcomparative
89 laboratorytestsofpotencyonthethreeavailablepreparations. Whiletheintentionof
providingacheaperproductwaslaudable,thestudystruggledtorecruitsufficientpatients
90 withonly14casestreatedfrom12differentLondonhospitalsduringthewholeof1933.
studiescanthereforeatbestbeclassedasinconclusive,andtheperformanceoftheTTCin
93 recruitingcaseswaspoorandalthoughfurthertrialistswerecontacted,itwastoolate.
PerhapstheMRCfeltanobligationtostudytheOrganondrug,havingrefusedanimport
88
T.R.ElliotttoF.H.K.Green(21December1933),T.R.ElliottFiles,WIGC/42TTC 193334.
89
ClinicalTrialsofExtractsofSuprarenalCortex(6February1934),T.R.Elliott Files,WIGC/42,TTC193334,13/1.
90
F.H.K.GreentoT.R.Elliott,(30April1934):T.R.ElliottFiles,WIGC/42,TTC 193334.
363
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94 licenseofthatfirmsinsulininOctober1923. Thefailureofthestudymaybeascribedto
throughitssubcommitteemembersA.S.ParkesandChassarMoir,butitwasdifficultto
96 collectadequatedata.HombreolwasalsostudiedatGuysHospital, andSt.
BartholomewsinLondon,Edinburgh,Manchester,inpatientssufferingrepeatedabortion,
97 98 prostaticcases,andchronicinterstitialmastitis. Oncemoreoverallresults were
inconclusive,buttheEdinburghdatawasatleastsubmittedtotheBritishMedical
99 Journal. By1934theactiveprincipleprogesteronehadbeenisolated,butithadtobe
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OxfordwhereProf.J.A.Gunnperformedphysiologyexperimentstoconfirmitspowerful
101 pressoreffectandfoundadrenalinlikeeffectsontheintestineandrabbituterus.
Publicationofhisstudywasheldupattheendof1937untilCIBAmadedecisionsona nameforthedrug,andwhethertheywouldmarketit,astherehadbeensomeminorsafety
102 issues. Bythefollowingyearastudyof150patientshadbeencompletedinLondon 103 confirmingthesharprisesofbloodpressureandalsoutilityinasthmapatients. Schering
Inconclusion,despitetheTTChavingamajorinterestinorganotherapy,theyfailed toestablishsuccessfulclinicaltrialswithseveralorganextracts.Allpreparationssentto themwereacceptedforevaluation,evenwhenalternativeversionswerealreadyavailable commercially.TheTTCdidnotadheretotheirpromisetoexamineonlynovelagentsand onseveraloccasionstestedpreparationssimplytoensurethataBritishversionwas available,whileallowingtestingofforeignpreparationsfromOrganonoftheNetherlands andCIBAofSwitzerlandwhentheythoughtthiswouldreduceprices.TheTTC recognisedtheproblemswithearlyextractsbeingofvariableandoftenweakpotencyand theywereflexibleintheirapproachtoevaluatingnewextractsthatofferedgreaterpotency. Theironlyrealsuccesswaswithoestrone,andthiscorrelatedwiththeparalleldevelopment oftheunderstandingoftheactiveingredientsandultimatelywiththeirsynthesisand manufacturebypharmaceuticalfirms. 8.4.4PerniciousAnaemia.
101
TTCMinutes9,(14July1938),MRCFile1523/15Gunnwasstilltestingitin1939, TTCMinutes10,(28March1939). 102 F.H.K.GreentoT.R.Elliott,(13October1937)andT.R.ElliotttoF.H.K.Green (15October1937),T.R.ElliottFiles,WIGC/42TTC193542. 103 Thecontinueduseofthecodenamewasunderstandableinthelightofthechemical nametrimethoxybenzyldihydroimidoazolhydrochloride.Preparation2020forraising BloodPressure,PharmaceuticalJournal 140(26February1938):211. 104 TTCMinutes4,(undated,1933)TTCMinutes5,(5March1934)TTCMinutes6, (28February1936),MRCFile1523/15.
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DrugHouses,BurroughsWellcome,OxoandGlaxo.Giventhepreviousconflictsonthis project,theTTCmaintainedthatdoctorspreferredtoreceivesamplesviatheMRC,rather
106 thandealingdirectlywithafirm. Despitethis,WilkinsoninManchestercontinuedto
105
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arguedthatCalciferol,(vitaminD2)couldalsobeconsideredsynthetic,thoughitdidnot originatefromelementarysubstances.Meanwhile,BurroughsWellcomedecidedto
111 manufacturethesyntheticvitaminandissuedsuppliesinSeptember1934. Thenitwas 112 recognisedthatirradiatedmilkofferedthebestadministrationofvitaminD. Szent 113 GyorgysvitaminP(citrin)wasalsoprepared andsenttoDr.MacFarlaneandDr. 114 SylvesterZilvaattheListerInstituteforexperimentalwork. Prof.NoahNorris
110
F.H.KGreentoT.R.Elliott(19February1935),T.R.ElliottFiles,WIGC/42 TTC193542.
111 112
STCMeeting,(19May1933),WF:STCS/G/49. DosageofVitaminDBritishMedicalJournal (17November1934):907. 113 STCMeeting,WCRLReport,(22January1937),WF:STCS/G/50. 114 STCMeeting,(22January1937),WF:STCS/G/50F.H.K.GreentoT.R.Elliott, (19February1935),T.R.ElliottFiles,WIGC/42TTC193542. 115 H.H.DaletoF.H.K.Green(8July1938),T.R.ElliottFiles,WIGC/42TTC 193542
116
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personfromthiscountrytomeetDomagkatBayer,andtosharehisfindingbefore
118 publication,whichwasdelayedforayear. AftertheTTChadfocussedforfouryears
Dalewasastoundedtohearthestorythathe(Colebrook)hadtakentheinitiativeand
121 goneovertoElberfeldandcorroboratedhisversionwithFrankGreen. Nevertheless,
theCommitteeagreedtoallowColebrooktoinvestigateProntosileventhoughElliott remarked:wewillnevergetconvincingclinicalevidencewhenareportismadebyonly
122 oneman. 123 Prof.CharlesCyrilOkell, ProfessorofBacteriologyatUCHsince1930,having
workedinthelaboratoriesofBurroughsWellcome,notedthatHopefulresultson
117
Domagk(18951964)qualifiedinmedicinein1921andtrainedasabacteriologist. HewasappointedasDirectorofResearchatIGFarbenin1927:R.A.Kyle,M.A. Shampo,GerhardDomagkJAMA 247(14May1982):2581. 118 H.H.DaletoA.LandsboroughThompson,(17February1967),93HD47.5.151. 119 F.H.K.Green,G.Covell,MedicalResearch,chapter7inA.S.MacNalty(ed.), HistoryoftheSecondWorldWar(London:HMSO,1953):258271E.J.Lowbury, LeonardColebrook(18831967)BritishMedicalJournal 287(1983):19813J.L.Turk, LeonardColebrook:theChemotherapyandControlofStreptococcalInfectionsJ.Roy. Soc.Med87(December1994):72728.
120
CharlesCyrilOkell,ObituaryBritishMedicalJournal (18February1939):362.
368
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manwithbrainsandperhapsacriticaljudgementbuthasbeenspoiledbysuccessin practice.Hewritestoopubliclyeverythingthathetouchesistherightthingbecausethe
127 kinghastouchedit. Prof.C.H.BrowninginGlasgowinvestigatedProntosil,andDr.
AlexanderJoeattheNorthWestFeverHospital(inEdinburgh,)treatedcasesoferysipelas andscarletfever,thoughwithdiscouragingresults.Londonstwofeverhospitalstreated
128 casesofgonorrhoeawithBayersUleronformulationofProntosil. InMarchof1936, 129 GreencontactedW.R.SnodgrassinGlasgow, andhetreated60erysipelascases,while 130 Prof.Ellisagreedtotreatcasesofarthritis. Wilkieshowedremarkablygoodresultsin 131 somecases.
124
T.R.ElliotttoF.H.K.Green,(8May1935),T.R.ElliottFiles,WIGC/42TTC 193542.
126
TTCMinutes6,(28February1936),MRCFile1523/15. TTCMinutes7,(11February1937),MRCFile1523/15.
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ThomasHenrymadeProntosilattheWCRLfortrialatWPRL,andapatentsearch
132 wassetunderwaytoseewhetheritwasprotected. Althoughitwasasimplederivative
ofadyeintermediate:evenifitprovedtobeunprotectedBurroughsWellcomedoubted whetheritcouldbemanufacturedsuccessfullyincompetitionwithadyeworks,andthere
133 wasevidencealreadyofRochepatentactivity. However,J.TrfoulatthePasteur
Instituteshowedthatthecolourlessparaaminobenzenesulphonamidewastheactivepartof
134 Prontosil,andasithadbeendescribedin1908,itwasunprotectedbypatents. Alarge
batchofthisbasecompoundwasmadeatDartfordbyaprocesssuppliedbytheWCRL, fortestsonlargeranimals,forclinicaltrials,andasastartingpointforpreparingfurther
135 similarsyntheticderivatives. Thefirstofthesetobeofferedfortestingwas 136 diaminodiphenylsulphone. BurroughsWellcomeofferedBritishmadeProntosiltothe
TTCasthematterwasurgent,inviewofpossiblesimilaractionbyanotherfirmTrevan suggestedthatifthetrialwereagreed,fulldetailsofthepharmacologicalresultsatthe
137 WPRLwouldbesupplied. On1October1935,theyheardthattheTTCwerealready
examiningmaterialfromanothersource(Bayer).G.A.H.Buttle,whoworkedunder TrevanattheWPRL,sentalettertotheSecretaryoftheTTCregardingpreliminary
138 experimentswithProntosilinmeningococcalbacteria(acauseofmeningitis). Burroughs
132 133
STCMeeting,(12July1935),WF:STCS/G/50. IGpatent430,580waspossiblyanticipatedbyRo149,428,STCMeeting,(15 November1935),WF:STCS/G/49. 134 M.Weatherall,InSearchofaCure:aHistoryofPharmaceuticalDiscovery (Oxford:OxfordUniversityPress,1990):150153. 135 STCMeeting,(13March1936),WF:STCS/G/50. 136 ReportofWCRL,(January1937),WF:STCS/G/50. 137 STCMeeting,(29May1936),WF:STCS/G/50. 138 G.A.H.Buttle,R.A.Q.OMeara,TheModeofActionof betaaminobenzenesulphonamideandProntosilinhaemolyticStreptococcalInfections Lancet(5December1936):132326.
370
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wellwrittenandprovokedsignificantdebateattheTTC,incurringfurtherdelays.
140 DalediscussedthepaperwithAndrewesandKingandresolvedseveralerrors.
alreadysenthiscommentsdirectlytoGreen: SinceMellanbyissatisfiedwiththispaperIagreetoitsimmediate publication.Iwasn'tmuchimpressedbythefirstpaper,andIregrettedthe outburstofexcitementinthepublicpressaboutthediscovery,whichwas onlyanextensionoftheGermanwork.Someofthecasesinthesecond paperareindeedcertainlymoststriking.But,thewriting,withitsitalicsand excitedadjectives,remindsmeofQueenVictoria's'Leavesfromahighland diary' afterwhichpage10dragsonedownwithasadbathus.(Sic).This page10mustberewritten.Iremainalittlesceptical,andIwonderwhether
139
T.R.ElliotttoF.H.K.Green,(8May1936),T.R.ElliottFiles,WIGC/42TTC 193542.
140
F.H.K.GreentoT.R.Elliott,(22May1936),T.R.ElliottFiles,WIGC/42TTC 193542.
141
T.R.ElliotttoF.H.K.Green,(29May1936),T.R.ElliottFiles,WIGC/42TTC 193542.
142
L.ColebrooktoF.H.K.Green,(29October1936),F.H.K.GreentoT.R.Elliott, (29October1936),T.R.ElliottFiles,WIGC/42,TTC193542.
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EvansSons,Lescher&WebbandBurroughsWellcomealsoforwardedpreparationstothe
146 TTC.
encouragedtheGovernmenttoinvest30,000in1936inthepreparationofchemically
143
T.R.ElliotttoF.H.K.Green,(28October1936),T.R.ElliottFiles,WIGC/42, TTC193542.
144
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IhavedescribedhowBurroughsWellcomebeganpreparingProntosilasearlyas 1936.Nopatentcouldbetracedforthewatersolublesulphonamide,whichBurroughs
150 WellcomealsopreparedasSoluseptasinein1936. Thisandsimilarproductsappeared
inpublicationsasMay&BakeralsopreparedanintramuscularformofSoluseptasineand
151 anoralform,proseptasine.
ProntosilasM&B576inJanuary1936.ByMay1937BurroughsWellcomesSulphP, versionofProntosilwasbeingusedforotitismedia,mastoiditis,rheumaticfever,
148
MRCAnnualReport19367,(1937):915referstoNIMR588/6memoThePresent PositionandFutureDevelopmentofBritishResearchWorkinChemotherapy(17March 1936). 149 MRCMinutesIII,(20March1936):47. 150 G.M.Roberts,SoluseptasineandSulphapyridineinMeningitisDuetoPfeiffer BacillusBritishMedicalJournal (25November1939):1041ATableof Sulphonamides,Chemist&Druggist146.1(14September1946):33637Soluseptasine andProsephasineBritishMedicalJournal (27March1937):666. 151 STCMeeting,(19November1937),WF:STCS/G/50. 152 STCMeeting,(7May1937)WF:STCS/G/50. 153 J.Slinn,AHistoryofMay&Baker18341984(Cambridge:HobsonsLtd., 1984):100,124.
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meningococcalmeningitis,puerperalsepsisandthesofttissueinfection,erysipelaswith
154 greatsuccess.
thepharmacologicallaboratoriesofthePharmaceuticalSocietyfortestinginmice,andit
156 wasmadegenerallyavailableinSeptember1938assulphapyridine. Therewassome
adversecriticismofM&B693bytheAmericans,butColebrookresolutelydefendedthe
157 sulphonamides.
hadnoexactinformationontheincidenceoftoxiceffectsthoughhehadseentwocases
160 ofagranulocytosis,ordepletionofthewhitebloodcells. Therelationofdosageto
154 155
STCMeeting,(24May1937),WF:STCS/G/50. H.H.DaleArthurJamesEwins,BiographicalMemoirsofFellowsoftheRoyal Society 4(1958):8191L.E.H.Whitby,Lancet(26May1938). 156 J.Slinn,(1984):122125H.J.Barber,HistoricalAspectsofChemotherapy:Six Essays(May&Baker,1978):27. 157 P.H.LonginIagoGaldston,BehindtheSulfaDrugs.AShortHistoryof Chemotherapy (NewYork:AppletonCentury,1943)P.H.Long,E.A.Bliss,The ClinicalandExperimentaluseofSulfanilamide,Sulfapyridine,andAlliedCompounds(New York:MacMillan,1939)
158 159
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toxicitycertainlyneedstobecarefullystudied.Itisalittledifficultinourcasesassomany
161 ofthemhavehadacertainamountofsulphanilamidebeforeadmission.
ButtleandTrevanworkedonadiacetyldiaminodiphenylsulphonederivative,whichwas
165 senttoProf.GarrodatSt.Bartholomews, whileclinicaltrialsofsulphonamide
161
L.ColebrooktoF.H.K.Green,(11May1939),T.R.ElliottFiles,WIGC/42, TTC193542.
162 163
STCMeeting,(24May1937),WF:STCS/G/50. SulphonamideBDH,PharmaceuticalJournal (13February1937):187 Sulphonamidecompounds:aSummaryofRecentReports,PharmaceuticalJournal (25June 1938):66566. 164 STCMeeting,(31January1939),WF:STCS/G/50. 165 J.H.Gaddum,JohnWilliamTrevanBiographicalMemoirsofFellowsofthe RoyalSociety 3(1957):275. 166 C.L.Oakley,NoteonProntosilPoisoninginMiceBiochemicalJournal 31 (1937):729730AnOutlineofChemotherapySulphonamidesPharmaceuticalJournal 142(29April1939):44344.
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167 productandtheydecidedtoadvisetowithdrawapplicationtotheMinistryofHealth.
Atthe1939BritishPharmaceuticalConference,chairmanJ.RutherfordHill calledfor
168 clinicalexperiencetestspriortodefiniteauthoritativerecognition. Hisconcernwas
thatBritainwasstillfightingabattleagainstpatentmedicinesandcarelessmanufacturers recallingthatthishadbeenongoingsincetheearlyeffortsofProfA.J.Clarkandthatthe 1914SelectCommitteehadwarned: Britishlawispowerlesstopreventanypersonfromprocuringanydrug,or makinganymixture,whetherpotentorwithouttherapeuticactivitywhatever (aslongasitdoesnotcontainascheduledpoison),advertisingitinany decenttermasacureforanydiseaseorailment,recommendingitbybogus testimonialsandtheunwantedopinionsandfacsimilesignaturesoffictitious physicians,andsendingitunderanynamehechooses,onthepaymentofa 169 smallstampduty,foranypricehecanpersuadeacredulouspublictopay. TheVenerealDiseasesActof1917representedtheonlyrealprogressthathadbeenmade againstsuchremedies. BecauseofthepublicitygeneratedbyProntosil,British firmsfoundreadytakersfor theirnewsulphonamidesanddidnotneedtoevaluatethemthroughtheTTC.Thiswasan importantmilestoneinthedevelopmentandtestingofthesyntheticBritish pharmaceuticals.Whenphysicianswereconvincedoftheactivityofinsulin,synthetic oestroneandsulphonamides,theywerekeentoparticipateinclinicaltrials.
167
T.T.C.Minutes6,(28February1936)andT.T.C.Minutes10(28March1939), MRCFile1523/15.
168
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TheTherapeuticTrialsCommitteeoftheMRC
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inJuly1936,importedundertheTherapeuticSubstancesAct,whichHarrisonexaminedat St.ThomasHospital,buthisstudiesdraggedonforeighteenmonthsandwerestill
172 inconclusive.
F.H.K.GreentoH.H.Dale,(9January1936)TTC.Minutes5,(5March1934) MRCFile1523/15.
173 174
377
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theintroductionofNeocryl.MostoftheSTCmembersfelttherewouldbeconsiderable
178 demandthoughJowettfeltsaleswouldbeunremarkableattheprice. Burroughs
WellcomesNeocryl,(Crylarsan)wastestedinabout100casesofneurosyphilis,butno clinicianstreatedmorethanahandfulofcasesandasaresultnonehadsufficientcasesfora
179 publication. TheTTCwereconvincedthatthedrugwaslessactivethanTryparsamide,
FurtherconfirmationcamefromanotherofYorkesformercolleagues,Dr.F.Murgatroyd
181 intheGambia. InviewoftherenewedinterestinNeocrylandthecompetitiveprices,the 182 BurroughsWellcomestrategywasthatitwasonlytobesoldondemand. However,
thedecisionwasshortlivedasin1938theydecidednottodoanyfurtherclinicalworkon
183 Neocrylbecauseofsafetyissues. Incomparisontothesulphonamide,thearsenicals
werenowapooralternative.
W.YorketoF.H.K.Green,(15June1937),T.R.ElliottFiles,WIGC/42,TTC 193542.
181
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from1931to1939andallowsanassessmentofhowmanyproductsweresynthetic,or otherwisenoveldrugsandhowmanywerecopiesofdrugsdiscoveredelsewhere.The generalgrowthofBritishpharmaceuticalmanufacturingbetween1919and1931was describedinchapter5. Inthe10yearsthattheTTCwasinexistenceatotalof59productswereacceptedfor testingasnotedintheformalminutesoftheirmeetings.Therewerethreeoccasionswhen twocompaniessubmittedidenticaldrugs,makingatotalof62drugstested.Thesewere providedasfollowsBoots9,BurroughsWellcome8,BritishDrugHouses7,CIBA (Switzerland)4,May&Baker3,E.Merck(Germany)3,Organon(Netherlands)3, HoffmannlaRoche(Switzerland)3,Bayer(Germany)3,Napp(UK)2,ImperialChemical Industries(UK)2,ParkeDavis(USA)2,WilcoxJozeau1,ABCM1,EliLilly(USA)1, Beiersdorf(Germany)1,Glaxo1,Merck(USA:NewJersey)1,Chase(France)1,Cilag (Switzerland)1,BoakeRoberts(UK)1,Schering(Germany)1,UpsterSmith(USA)1, independent1,SmithKlineFrench(USA)1.TheEdinburghbasedcompaniesdidnotuse theTTCandtheirmaininteractionwaswiththeResearchlaboratoryoftheRoyalCollege
184 ofPhysiciansinEdinburgh.
inJuly1931,buthissonboughtanewsiteatBulwellontheoutskirtsofNottinghamand
187 returnedBootstoBritishcontrolagainin1933. Thefirmhadeffectivelybeenin
Americanhandssince1920whenJesseBootacceptedanofferof2.25milliontosellthe
184
EdinburghManufacturingHousesPharmaceuticalJournal 141(20August1938): 1634. 185 TTCMinutes5,MRCFile1523/15,(5March1934). 186 TTCMinutes1,MRCFile1523/15,(8July1931). 187 ChristopherWeir,JesseBootofNottingham.FounderoftheBootsCompany (Nottingham:TheBootsCompany,1994):601R.P.T.DavenportHines,J.Slinn. (1992):97.
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manufacturersofinsulinandhadanunrivalledanalyticaldepartmentwithinaplantof14
189 acresandmorethanamillionfeetoffloorspace. TheBootsPureDrugCompanyhad8
Harmolusefulforangina,whengivensubcutaneouslybutitcausedirritationandhadlittle
191 effectwhengivenorally,andlargerdosescausedcolic. ThiswasthereasonthatBoots
188
BootsDrugsBusiness.ReasonsfortheAmericanAmalgamationTheTimes(5 July1920):25. 189 JonathanLiebenau,TheMRCandthePharmaceuticalIndustryinJoanAustoker andLindaBryder(eds.),(1989):179. 190 TTCMinutes3,(8July1932),MRCFile1523/15J.C.Bramwell,J.M.H. Campbell,W.Evans,HarmolHClandonPropylharmolLactateinAnginaPectoris Lancet(8July1933):69G.K.Elphick,J.A.Gunn,Quart.J.Pharmacology (1932):37.
191 192
380
TheTherapeuticTrialsCommitteeoftheMRC
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ThomasandQueenCharlottesinLondonandTheLondonHospital,theNationalHeart
195 HospitalandinEdinburgh,CambridgeandManchesterbutwithoutrealsuccess. Onthe
andE.M.BavinofBootsperformedpotencytestsontheirheparinpreparationand
198 collaboratedwith theNIMR,butitwasnotsenttotheTTC.
381
TheTherapeuticTrialsCommitteeoftheMRC
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systemically.Bootseventuallygaveuptheireffortsonantisepticsandtheytooprepared
199 sulphonamideantibioticderivativesafterthediscoveryofProntosil, patentinga
sulphonamideantibacterialwithincreasedstability,Psulphonoamidobenzamine,whichwas shownbytheNIMRtobethefirstagenttocuremiceinfectedwith Salmonellatyphi. UnderPymansdirectionaseriesofglycerophosphatessalts,histidinepreparations, glyoxalines,isoquinolines,arsenicderivativesandavarietyofamidinesweresynthesised andhisteamevaluatedlocalanaesthetics,antiseptics,pressordrugs,antimalarials, hypoglycaemics,purgatives,acridinesandorganicsaltsofbismuth200 Pymangavean insightintoBootsresearchinhispapertotheSCIon13May1935.Heexplainedthe chemistrybehindHarmolandthepreparationofbismuthinoilandtheimproveddrugsthat
201 werenowavailabletoreplaceSalvarsan,suchasStabilarsan,amorestableform.
199
S.A.B.Kipping,(1963):302310.Bootsproducedpatentsonsulphonamide derivativesin1940and1942,H.King,(1944):681697. 200 H.King,FrankLeePymanObituaryNoticesofFellowsoftheRoyalSociety 4 (1944):681697. 201 F.L.Pyman,PharmaceuticalJournal (25May1935):619. 202 J.Slinn(1984):1001.
382
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NeitherHalarsolnorParosanwerementionedinSlinnsHistoryofMay&Baker,norin the1948BritishPharmacopoeia,indicatingtheywereprobablydroppedthoughPyman
205 referredtoHalarsolin1935.
themtomaximisethenewopportunityofferedbyM&B693.ThisisthefirstcaseIhave foundofaBritishpharmaceuticalfirmrecruitingaphysicianspecificallytoperformclinical trials.May&BakerputtheirrequesttotheABCMforadoctoraged30to35years: whocouldputinahalftothreequartersofhistimeattheworksofthe firm,andtherestofthetimedoinghospitalwork.Thelatterwouldhaveto bedonesomewhereeastwardsofLondoninorderthatthedoctorwouldnot havetospendtoomuchtimetravelling.Theworkwouldberelatedto venerealdiseasetreatmentanditwouldbethereforebeadvantageousifthe 207 hospitalworkcouldsimilarlybesorelated. Althoughnobodywasimmediatelycametomind,LandsboroughThompsonwrotetoPratt oftheABCMthat: thefactthatatleasthalfthemanstimewillbetakenupsuggeststhatheis todosomethingmorethanadviseonclinicalquestionsanddealwith
203 204 205 206
383
TheTherapeuticTrialsCommitteeoftheMRC
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208
A.LandsboroughThompsontoJ.D.Pratt,(20September1935),ABCMMRC File1523.
209
A.LandsboroughThompsontoJ.D.Pratt,(24September1935),ABCMMRC File1523.
210
J.D.PratttoA.LandsboroughThompson,(27September1935)ABCMMRC File1523.
211
384
TheTherapeuticTrialsCommitteeoftheMRC
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oftheTTC,theSTCreviewedalloftheirproductssinceneoavenylin1925todecide
215 whichtosubmitfortrials.
213
CommunicatedfromH.A.D.JowetttoG.Pearson,(25February1931)andG. PearsontoC.M.Wenyon,(25March1931),WF:STCS/G/49.
214 215
385
TheTherapeuticTrialsCommitteeoftheMRC
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AllofthethreecardiovascularproductsthatBurroughsWellcomesubmittedtothe
216 firstTTCmeetingwereacceptedfortrials.Inadditiontoergotoxineethanesulphate, 217 theseweredigoxinanddigitalinumverum(diginutin),discoveredinAugust1929. There 218 werenewderivativesofDigitalis,whichhadbeenusedasanextractforcenturies.
216
386
TheTherapeuticTrialsCommitteeoftheMRC
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weeksWenyonarrangedpreparationofcommercialsuppliesofergometrineatBurroughs
224 225 Wellcome. Afavourablereportledtocautiousreferenceinthecompanyliterature. 226 BothAllen&HanburysandBDHsoonfollowed. ChassarMoirperformedfurther 227 clinicaltestsonergometrineandconfirmeditsactivity. SomeyearslaterMoirrecalled
223
C.Moir,H.H.Dale,TheActionofErgotPreparationsonthePuerperalUterus:a ClinicalInvestigationwithSpecialReferencetoanActiveConstituentofErgotasyet UnidentifiedBritishMedicalJournal (18June1932):1119 H.Dudley,J.C.Moir,The SubstanceResponsiblefortheTraditionalClinicalEffectofErgotBritishMedicalJournal (16March1935):52023,53233J.C.Moir'IntrinsicDysmenorrhoeaProceedingsof theRoyalSocietyofMedicine29(1936):950P.M.Dunn,JohnChassarMoir(1900 1977)andtheDiscoveryofErgometrine Arch.Dis.Child (FetalNeonatalEdition)87.2 (2002):F1524In1935MoirmovedtotheHammersmithhospitalandin1937became thefirstNuffieldProfessorofObstetricsandGynaecologyinOxfordandamemberofthe MRCCommittee.
224
STCMinutes,(12July1935),WF:STCS/G/49ErgometrineBritishMedical Journal (4May1935):929. 225 STCMinutes,(7October1936),WF:STCS/G/49WalterSneader:(1985):108 110. 226 ErgometrineBritishMedicalJournal (25May1935):1075. 227 C.Moir,ClinicalexperienceswiththenewalkaloidergometrineBritishMedical Journal (24October1936):799801E.M.Tansey,Ergottoergometrine:anobstetric renaissance?ClioMed.61(2001):195215. 228 J.C.Moir,TheObstetricianbids,andtheuteruscontractsBritishMedicalJournal (1964)ii:10259,quotedinP.M.Dunn,JohnChassarMoir(19001977)andthe discoveryofergometrineArch.Dis.ChildFetalNeonatalEd(September2002):F15254.
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Germany,bythepharmacologist,SchmiedebergandBayerhadevaluatedacompound calledHedonalin1899,butfoundsomeminortoxicityissuesandtheirpatentsexpiredin
230 1913. In1934aBritishcliniciannotedthesimilaritiesbetweenthesymptomsoftherare
paralyticdisordermyastheniagravisandthepoisoningbycurare,forwhichphysostigmine wasanantidote,soshetrieditonapatientwiththediseaseandachievedexcellent
231 results. AlthoughtheBurroughsWellcomeversionwasinitiallyreportedby Trevanto 232 233 beunsatisfactoryinthelaboratory,itwasbeneficialinmyastheniagravis. Ryle in
Cambridgeagreed,butthoughttherewaslittleadvantageoverpituitaryextract
234 235 (pituitrin): FrancisFraser,atSt.BartholomewsandE.ArnoldCarmichael atthe
WalterSneader,(1985):11617. STCMeetings,(5April1935)and(12July1935),WF:STCS/G/49Walter Sneader,(1985),27,337338. 231 WalterSneader(1985),118. 232 STCMeeting,(7October1936),WF:STCS/G/49. 233 D.Porter,ChangingDisciplines:JohnRyleandtheMakingofSocialMedicinein Britaininthe1940s,Hist.Sci.30(1992):13764Hewasinchargeofthelabsetup undertheEPHLS,theemergencyPublichealthservice:GeoffreyTweedale,AttheSignof thePlough:275YearsofAllen&HanburysandtheBritishPharmaceuticalIndustry1715 1990(London:Murray,1990):36. 234 J.RyletoF.H.K.Green,(30May,1933),MRCFile1523/21. 235 E.A.CarmichaelhadreceivedanM.R.C.grantin1926forresearchoncerebral glioma,M.R.C.MinutesII,(22October1926):16,181.
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probablyamongthemostsuccessfulbytheTTCintermsofgeneratingdataand
237 publications.
BurroughsWellcomealsosentpreparationsofIndianephedrineand pseudoephedrinetotheTTCforevaluation.G.W.BrayandL.J.Witts,NuffieldProfessor
238 ofMedicineinOxford treated52coursesin18patientswithephedrineand49coursesin 239 20controlpatients. Wilkiereportedthatingeneral,pseudoephedrinewasnotasgoodas
E.H.Carmichael,S.R.Fraser,D.McKelvey,D.P.D.Wilkie,Lancet(5March1934): 342.
237
J.AustokerandL.Bryder(eds.),(1989):214,220,2234,236.RylenotedWitts whenhewasayoungclinicianatGuyshospital.In1934hereceivedMRCsupportforhis researchonsplenicanaemia.HebecamethefirstNuffieldProfessorinOxfordandlater editedoneoftheearliestbooksonclinicaltrials,L.J.Witts(ed.),MedicalSurveysand ClinicalTrials:SomeMethodsandApplicationsofGroupResearchinMedicine(London: OxfordUniversityPress,1959). 239 TTCMinutes2,(15January1932),TTCMinutes3,(8July1932),MRCFile 1523/15G.W.Bray,L.J.Witts,PseudoephedrineinAsthmaLancet(14April1934): 788790. 240 TTCMinutes2,(15January1932),MRCFile1523/15. 241 T.R.ElliotttoF.H.K.Green,(9February1934)andF.H.K.GreentoT.R. Elliott,(21February1934),T.R.ElliottFiles,WIGC/42TTC193334J.B. Christophersen,M.Broadbent,EphedrineandPseudoephedrineinAsthma,Bronchial AsthmaandEnuresis,BritishMedicalJournal (2June1934):97879S.B.Dimson,The PressorActionsofEphedrineandPseudoephedrineinManQuarterlyJournalofPharmacy andPharmacology 7(1934):23J.E.Monro,EphedrineandPseudoephedrineinSpinal Anaesthesia,QuartJ.Pharm.7(1934):32.
242
STCMeeting,(1October1936),WF:STCS/G/50.
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LancetandBritishMedicalJournalarticles,BurroughsWellcomepreparedpropagandaon Blaudspills,whichtheyalreadysold,asastableferrouspreparation,whichinthepresence
243 ofgastricjuiceproducedferricchloride. EvenbeforeTrevanarrangedclinicaltrialson
histidinehydrochlorideforthetreatmentofduodenalulcersitwassuggestedtoreleaseit
244 onthebasisofpublicationselsewhere. Onasimilarbasistheymarketedarylestersof
hydnocarpusoilacid,andCarbasone.ThelatterhadnoUKpatentnorhadatradename
245 registered. Theyfelttherewassufficientevidencefortannicacidjellytojustifyplacingit
onthemarketinCanada.TheseproductswerenotsenttotheTTCastheywereprepared inresponsetoaperceivedclinicalneed,andcouldbesoldonthebasisofgeneral publications. On19May1933theABCMwrotetoBurroughsWellcomeagainaskingaboutthe possibilityofcollaborationwiththeDSIR.246 BurroughsWellcomefeltthat:while progressindevelopmentofbiologicaldrugs(hormones,vitaminsandplantconstituents)is satisfactory,thediscoveryofnewsyntheticdrugsstilllagsbehindtheachievementsof foreigncountriesandisalmostwhollydependentuponforeigninitiativetheCommittee areoftheopinionthatifChemotherapyinthiscountryistoholditsownincompetition withforeigndevelopment,amoredefiniteorganisationthanthatindicatedintheABCM letterisrequired.Thisquestionshouldbeconsideredfromthepointofviewof 1. Thepossibilityofcooperationamongindividualfirmsandifpossible,thenatureof thiscooperationanditsrelationshiptotheDSIR. 2. TheparttobetakenbyGovernmentDepartmentsand
247 3. Thekindofresearchtobeundertaken.
TheDSIRoutlinedtheirongoingresearchandthesepointswerediscussedatthe STCmeetingon14July1933.Oneofthemainareasofcollaborativeworkproposedwas
243
TheAssimilationofIronLancet(4September1937):588TheActionofIron BritishMedicalJournal (13November1937):970971 Proc.Roy.Soc.Med. (March 1933):607STCMeetings,(19May1933)and(1October1936),WF:STCS/G/4950. 244 STCMeetings,(5April1935),(12July1935)and(1October1936),WF:STC S/G/4950. 245 STCMeetings,(19March1933),(24May1934),STCMeeting,(1October1936), WF:STCS/G/4950. 246 14July1933,WF:STCS/G/49. 247 14July1933,WF:STCS/G/49.
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themembersoftheCommitteedesiretoplaceonrecordtheirsenseofthe greatlosstheCommitteehavesustainedbythedeathoftheiresteemed colleagueDrJowettwhoseripeexperienceandsoundjudgementwere 249 alwaysofthegreatestvalueintheirdeliberations. IntheWCRLreportofJanuary1937,Wenyondescribedextensiveresearchon virusdiseases,thedevelopmentofparasites,generalpathology,bacteriologyand parasitology,antileproticoils,antimalarials,streptococcalandmercurycompounds.The discoveryofsulphonamideshadrestimulatedinterestinthetherapyofallinfectious diseases. Avenylcreamwasamercurialpreparation,whichhadbeenusedinleprosyfor
250 years. Earlierin1931,BurroughsWellcomesentittoleprologistsinSudan,Korea,Cape
Province,SouthAfrica,andChinaandreceivedfullreports.Henry,SmithandTrevan summariseditspropertiesandthesupportingdataincludingstabilityattropical
251 temperatures. AvenylwasthensubmittedtotheTTCafterevaluationattheWPRLasa 252 possibleantisyphilitic. Afteraconsiderabledelay,theTTCagreedtoarrangestudiesof
248
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handledbytheTTC,andfinallyinDecembertheSTCon14Dec1934theTTCreporton
254 Avenylwasdiscussed. TheTTCquestionedwhethermercurialsofthistypewereeven
SnodgrasseventuallyperformedtheTTCstudyinGlasgowandshowedthat Avenylwasbetterthancalomelbuthedidnottopublishthedata,andasaresult
257 BurroughsWellcomedecidednottoadvertiseitforuncomplicatedsyphilis. Their
juniorchemicalassistants,twoattheexperimentaldepartmentatDartfordandoneatthe WCRLwhohelpedtosearchthechemicalandpatentliterature,freeingthechemiststo
254 255
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261 trytonegotiateasaleslicense.
In1936Benzedrineandotherephedrinederivativeswereevaluatedasanaleptics
262 (stimulants). Smith,Kline&Frenchhadmarketedtheseinaninhalerin1932foruseas
nasaldecongestants,andTrevansummarisedtheireffectinshorteningtheawakeningtime
263 ofanaesthetisedmice. BurroughsWellcomepreparedmodifiedversions,including
confirmed,incomparisonwithisomyn(Benzedrine)266,whichhadbeenevaluatedby BargerandDalein1910.Severalfirmsexaminedthesesympathomimeticaminesinthe
267 early1930s.
260
261
262 263 264 265 266 267
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antisepticsaftermouldswerefoundgrowinginpreparations.268 Trevanprepared
269 crystallineinsulinandsentanoteonthistoNatureandthePharmaceuticalJournal.
SamplesweresenttoHarrington,presumablyforhimtotrytosolvethestructureofinsulin
270 andsynthesiseitashehadwiththyroxine. Theydevelopedfurtherinsulinformulations, 271 havingLocalinsulintestedatGlasgowRoyalInfirmary. Everybatchofprotamine
insulinproducedwastestedinrabbitsattheWPRL,butnothavingsuccessinmakingthe insolublederivativeofProtamineinsulinate,itwassuggestedthiscouldbelicensedfrom
272 anotherfirm.
8.7.4.Glaxo. InthePostwarchapterIdescribedhowGlaxoevolvedfromNathansby incorporatingscientificconceptsintotheirfoodbusiness.After1931Glaxocontinuedto evaluatevitaminstoaddtotheirmilkproducts.Calciferolwasisolatedinpurecrystalline formin1932,allowingGlaxotoproduceevermoreconcentratedformsofOstelin,that couldbemorereadilystandardisedandwhichweremorestable.VitaminAwasfoundin milkfatandGlaxodevelopedaseriesofproductsrichinvitaminAincludingtheAdexolin lines,OstomaltandMaltoline.Theyalsoproducedvitamin enhancedfoodstuffsincluding Farexin1932.BacharachandJephcottfoundtheyneededtoeducateignorantdoctorsas
273 theytriedtomarketproductsthroughethicalchannels. However,whentheir
intramuscularcombinationformulationofvitaminsAandDwassubmittedtotheTTCin June1933,itwasinitiallyrejected,asGlaxogavenoclearindicationthatitwouldbebetter
274 thantheoralform. AnM.D.thesisprovidedbyGlaxowassaidbyEdwardMellanbyto 275 beabsoluterubbish. Dawsonstated:theconcentrateofvitaminsAandDfor 276 intramuscularusedoesnotimpressmemuch, andT.WattsEdenwasalso
268
STCMeeting,(27March1931):G.E.PearsontoC.M.Wenyon,(8June1931), WF:STCS/G/49. 269 STCMeeting,(19May1933),WF:STCS/G/49. 270 STCMeeting,(8May1929),WF:STCS/G/49. 271 STCMeeting,(18February1938),WF:STCS/G/50. 272 STCMeeting,(29May1936),WF:STCS/G/50.
273 274 275 276
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committee,whichranfrom 1929,disapprovedoftheSteenbockpatentstakenoutby
279 Glaxo. TheyfeltthatSteenbock,basedinWisconsinwasprofitingfromawidepatentin
astateofuncertainknowledgebasedonearlierBritishwork.FrankRobinsonjoinedthe
280 researchteamasachemistin1933.
GlaxoremainedprimarilyanutritionalproduceruntiltheestablishmentofGlaxo LaboratoriesinMarch1935,whenworkbeganonanewsitefor250staffinGreenford,
281 Middlesex. BythistimeJeffcottwasManagingDirectorandFarmerwasprogressingto
seniormanagement.Glaxoestablishedlaboratoriesforbacteriologyandforanalyticalwork, biochemistryandorganicchemistry,whichwerecompletedinSeptember1936and
282 occupiedtheupperfloor. Theyalsohadanampouleunitandtheirownuniqueglass
395
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396
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Perparineweredelayedfor6months,pendingresultsfromcontinentalworkersanditwas neveractuallytestedinBritain.Amongtheotheragentssubmittedfortestingjustbefore
290 theSecondWorldWarwasEupaverin, asyntheticpapaverinederivativefromMerck,
claimedtobelesstoxic.Merckhadfirstdiscoveredthisalkaloidfromopiumplantsin1848
291 aftermorphineandcodeinehadbeenremoved. AlthoughasGreenwrotetoElliott:
287 288
BritishChemicals:TheirManufacturersandTheirUses(London:ABCM,1927)
397
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AfterthediscoveryofcalciferolanditspreparationbyGlaxo,BDHsenttheirversion,
RadiostoltotheTTCfortestinginSheffield,London,andNewcastleinstudiescontrolled byXrays.MellanbyfounditsatisfactorybutwonderedhowitcomparedwithAmerican
295 irradiatedergosterol. BDHalsoaddedconcentratedvitaminstotheirmaltproductssuch
TheresultsoftheBDHinteractionwiththeTTCaredifficulttointerpret.Inonecase BDHwerelateincopyingaGermandruganditwasdifficulttosetupastudybecause Britishworkersnolongerusedthattypeofdrug,andintwocasestheygotclearfeedback whenproductswereeitheroflimitedvalueorledtosideeffects.Themajorityofthe studiesweresimplyinconclusive.Itappearsthattheearlysuccesseswiththyroxinand insulinwerenotbuiltupon.Aseriesofsyntheticdrugswereproduced,butoftenonly minorvariationsonexistingproductsandwithlittleobviousadditionalclinicalbenefit.It seemsthattheskillsthatCarrbroughtwereintermsoflargescalemanufacturingrather thaninnovation.However,theadvancesinmanufacturingcapacityallowedBDHto capitaliseonexternaladvancesastheyhadwithinsulinandtheirpreparationofsteroidsat inthe1930s.TheBDHannualmeetingin1935reportedthatnearly35,000hadbeen spentonanewfactorybuildingtoproducefinechemicalsandanewbiologylaboratoryand
294
V.Petrow,SirF.Hartley,TheRiseandFalloftheBritishDrugHouses,Steroids, 61:476482. 295 TTCMeeting2(13January1932)and4(undated1933)1523/15. 296 F.H.Carr,MolecularDistillationPharmaceuticalJournal 141(12November 1938):498. 297 TTCMeeting2,(13January1932)TTCMeeting3,(8July1932),MRCFile 1523/15.
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8.7.6Allen&Hanburys. Allen&HanburyspreparedinnovativeproductssuchasaHaliborange,which maskedthetasteofhalibutliveroilandincorporatedvitaminsA,C,andD.Intheearly 1930stheirgrowthcontrollinghormoneoftheparathyroidglandwastestedattheRoyal CollegeofSurgeonsandattheKingsCollegeforlimitingthespreadofcancerandan adrenalcorticalextract,EucortonewaspreparedforthetreatmentofAddisonsdisease. Inreviewingthestateoftheindustryin1935,Gambledescribedthestrategywithin Allen&Hanburys,withnewscientificproductswerebeingpreparedalongsidethe centuriesoldremedies: Whenwesurveytheprogressthathasoccurredinthisperiod,weseethatit is due to the introduction of new types of pharmaceutical products, which have required improvements of methods and plants. These have grown up alongsideoldproducts,whichhavecontinuedtobemanufacturedbytheold 300 methods,thoughoftenimprovedindetail.
GeoffreyTweedale,(1990):151.
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FrancisLeslieRose,whohadtrainedunderKippinginNottingham,joinedBlackleyin 1932,aftertrainingatUniversityCollege,Nottingham,includingaPhDpartsponsoredby
304 ICI. TheresearchmanageratICIwasMarmadukeBarrowcliff,alsoaNottingham
graduatewhovisitedfrequentlyalongwithhisAcademicRelationsOfficer.We encounteredBarrowcliffearlieratBurroughsWellcomeandBootshehadalsospentsome
305 timeinMalayainresearchonrubber. AlthoughICIdyestuffsputinrequeststotheTTC
fortestingacetyl6oxynaphthoicacidandquinadil,previouslyreferredtoassubmitted jointlywithBDH,theyalsoputforwardtheirownquindolinemethochlorideasan
306 antiseptic,butdecidedafterdiscussionswiththeTTCtowithdrawtheapplication. The
onspecialisedpharmaceuticalandmedicalproducts,whichwereexpectedtobecomean importantpartofthedyestuffsgroupactivitiesandwerecollaboratingwiththeLSHTMin
302
RobinsonhadmovedfromManchestertotakeupthechairatUniversityCollegein London.LordToddandJ.W.Cornforth,RobertRobinsonBiographicalMemoirsof FellowsoftheRoyalSociety 22(1976)415527. 303 PharmaceuticalResearchinICI193657(Macclesfield:ImperialChemicalIndustries Ltd.,1957):12.TheotherswereF.H.S.Curd,W.R.Boon,J.C.Lumsden,D.J. BranscombeandH.C.CarringtonandSamEllingworthledtheteam. 304 Obituary,FrankL.Rose,TheTimes,(5March1988)C.W.Suckling,Francis LeslieRose27June19173March1988BiographicalMemoirsofFellowsoftheRoyal Society 36(1990):491524. 305 ThelibrariansatAstraZenecaassistedmeinidentifyingthepatentstakenoutby Barrowcliff.Hisfirsthadbeenontrypanarsinitesin1908andhisfirstforICIwasin1934 (UKpatent408258). 306 TTCMinutes7,(11February1937),MRCFile1523/15. 307 C.W.Suckling,B.W.Langley,FrancisLeslieRose27June19093March1988 BiographicalMemoirsofFellowsoftheRoyalSociety36(1990):490524.
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abasicstudyofimmunisationThecompanyhadestablishedaresearchcounciland researchcommitteeswereintouchwiththeleadingscientistsinthecountry,including
308 chemistssuchasRobertRobinson,IanHeilbronandJocelynThorpe. Thefirst
Oneofthefastestgrowingproprietarymedicinemanufacturersinthe1930swas Beechamswhoreportedsalesof500,000in1936buttheydidnotproduceethical
310 productsofinteresttotheTTCwithsalesofthatmagnitudetheydidnotneedto. A. 311 BoakeRoberts&Co.ofLondon submittedjustoneproducttotheTTC,anamyl
salicylate(Abracide),whichwasanewphenolderivative,evaluatedbyWilkiesgroupin Edinburgh,whoshoweditseemedtorelievepainatonceanddecreasedsepsisinburns
312 patientsandhepreparedapaperfortheBritishJournalofSurgery. TheCommitteedid
notseemtomindthatWilkiesreportgaveratherapufftotheproprietaryantisepticas thecompanydeserveditforitwastheonlyantisepticwhichblendedwellwithamyl
313 salicylate. TheactualresultsweresecondarytowhattheCommitteethoughtofthe
compoundandinthiscasealettertotheBritishMedicalJournalwassuggested.
308
CommercialFirmsandResearch,PharmaceuticalJournal 140(30April1938):
460.
309 310
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ArequestbyNappofCambridgetohaveHepamult(liverextract)andProfundol (Progestin)testedwasdeclined,buttheformerwasstillmarketedasadrycalfliver
314 315 extract. Nappalsoproducedsanocrysin,whichhadbeentestedearlierbytheMRC.
Nevertheless,theircollaborationwiththeTTCwasfruitfulandledtofurthersignificant
316 interactionsfrom194248.
Evans,Lescher&Webbcontinuedtoproducevaccinesandantitoxinsbuthadno interactionstheTTCregardingnewdrugs.Bythemid1930stheywereoperatingatrading
317 profitof45,111. Theyoperatedquiteindependently,mostoftheirinteractionsbeing
withtheEvansBiologicalInstituteatRuncorn.In1935theypublishedpapersshowingthat
318 theyhadworkeduponthestorageofergotandthestandardisationofthyroidextracts.
ConsiderableextensionsweremadetotheEvansBiologicalInstitutein1937asthe companyproducedvaccinesforcholera,plagueandsmallpox,butalsotuberculins,heparin andhyaluronidaseandthesyntheticStreptocidesulphonamide. DuringthisperiodBritishfirmsattemptedforthefirsttimetoproducenoveldrugs, butdidsobyfollowingseveralparallelstrategies,eachfirmplayingtotheirownparticular strengths.BurroughsWellcomecontinuedtofavourphysiologyandalkaloidalextracts, manyfirmspurifiedandstandardisedhormonesandtookasimilarpathwithvitamins. Althoughtheybasicallyproducedthesameproducts,hormoneandvitamintherapywasan areawhereBritainwasaheadofGermany.Somefirms,andparticularlyBootsfrom1927, May&BakerandmostofallBritishDrugHousesemphasisedsyntheticdrugs. Howeveritmustberecognisedthatthenumberofnovelchemicalssynthesisedwas farbelowGermaneffortsandthemainemphasiswasonmarginalimprovements preparationofsynthetichormones,thyroxineanddiethylstilboestrol,oropticalisomers withenhancedactivityorbettertoleratedormoresoluble,evenlongerlastingsaltsof availabletherapies.Theseledtomarginalimprovementsbutafrustrationforthefirmswas thatitwasdifficulttoarrangestudieswiththeTTCtoshowthesebenefits,orperhapsthey
314
TTCMinutes5,(5March1934),MRCFile1523/15Preparations&Appliances BritishMedicalJournal (5May1934):950. 315 GoldPreparation Sanochrysin,BritishMedicalJournal (4May1935):927. 316 ThetwomaincollaborationsconcernedParpanit,MRCFile1523/71andIrgamid, MRCFile1523/66. 317 EvansSons,Lescher&Webb,PharmaceuticalJournal 134(9March1935):282.
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werejustinsufficient.Asaresultcompaniescontinuedtodevelopdrugsforthetropical marketandbegantoemploytheirownphysiciansasGlaxo,Allen&HanburysandMay& Bakerdid. Animportantconclusionalsoisthattheprocessesdevelopedforlargescale manufacture,forcrystallisations,enhancingpurity,developingbettersaltsandfor molecularmanipulationweretheskillsthatbenefitedBritishindustrywhensulphonamide antibacterialswerediscoveredandmanyBritishfirmswererapidlyabletodevelopbetter alternativestoProntosil.Whenevertherewasastepchangeinactivityaswithinsulinand Prontosiltherewasareadystreamofphysicianswillingtotestthem. 8.7.8.ForeignFirms. AswellastheeverpresentthreatoftheGermanfirms,theinterwarperiodwas markedbytheestablishmentofUSfirmsinBritain,thoughinitiallytheirinteractionswith theTTCwerelimited.Theyactedprimarilyassalesunitsforproductsdevelopedin America.KhellaviswasanewdrugsaidbyEgyptianworkerstoassistinremoving
319 calculi. UpsterSmith&Co.werebasedinMinneapolisandtheirversionofKhellavis
wassenttoWilkieinEdinburghin1933,whotreated3casesofuretericcalculi,oneof
320 whompassedastonebuttheothershadnobenefitandsufferedfromsevereflatulence. 321 Anothertrialistaskedtoparticipatefoundnocases. Eventuallyitwasconcludedthatit 322 wasnogood.
Smith,Kline,Frenchtriedtoestablishstudiesofpentanucleotidefrom1933through theirU.K.subsidiaryMenleyJames.TheTTCsentthedrugto6centresandDawson
323 treated3cases,showingitincreasedtheleucocytes Wilkieinvestigateditsrolein
increasingleucocytespriortosurgery,inmalignantneutropeniaandotherconditions
324 associatedwithneutropenia. GarrodatSt.Bartholomews,KnottatGuys,Wilkinsonin
ManchesterandWittsinOxfordwereinvolvedandpresentedcasestotheRoyalSocietyof
318
R.F.Corran,ThyroidstandardisationandStorageandEvansBiologicalInstitute, RuncornPharmaceuticalJournal(29June1935)78183. 319 TTCMinutes6,(28February1936),MRCFile1523/15. 320 TTCMinute4,(undated1933),MRCFile1523/15 321 TTCMinutes5,(5March1934),MRCFile1523/15. 322 TTCMinutes7,(11February1937),MRCFile1523/15. 323 TTCMinute4,(undated1933)TTCMinute5,(5March1934),MRCFile1523/15.
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AdovernfromRocheandTussipectfromBeiersdorfwerealsoturneddownwithnoreason recordedandHelborsidfromRochewasconsidered,butthecommitteedecidedtowaitfor
327 6monthsforresultsfromelsewhere,presumablyoverseas.
hydrochloride,wassenttoW.R.TrotteratUCHandalthoughheshowedavasodilator effectontheconjunctiva,thecompoundhadnegligibleeffectsonbloodpressureanditalso
329 hadunpleasanteffects,andthereforewasnotdeveloped.
J.C.SpenceofNewcastlecomparedthetwoforms,treatingfourcasesoneachtreatment withlittledifferencebetweenthem.ThiswasthenearestthattheTTCgottoacontrolled
324
TTCMinute6,(28February1936),MRCFile1523/15G.StewartSmith,ACase ofAgranulocytosisTreatedwithPentanucleotideLancet(16March1935):607. 325 L.J.WittsAgranulocytosisProc.RoyalSocietyofMedicine29(1936):671. 326 TTCMinutes5,(5March1934)File1523/15. 327 TTCMinutes7,(11February1937)File1523/15. 328 TTCMinute9,(14July1938),MRCFile1523/15. 329 TTCMinutes8,(7February1938)TTCMinutes9,(14July1938),MRCFile 1523/15. 330 TTCMinutes8,(7February1938),MRCFile1523/15.
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HoffmannlaRocheputforwardtheirSyntropanoramprotropine,introducedin 1933.Thechemicalstructurewasprovidedalongwithdetailsofpreliminarylaboratory
333 andoverseasclinicalstudies. Thiswasthefirstofseveralatropinelikemoleculeswhere
anattempthadbeenmadetoseparateoutthebeneficialpharmacologicaleffectsofthedrug
334 fromitssideeffects,suchascausingadrymouth. Thereferencesprovidedbythefirm 335 werehighlyeulogistic,suchasthebrilliantresultsofthisantispasmolyticin15cases.
1936.Itshowedgreatpromiseasabetterantispasmodicthanatropineandwitha
337 weakermydriaticeffect,lesseningtheproblemofdryeyes. BurroughsWellcome
consideredpreparationofSyntropan,buttheirstafftraceditspatentsothiswasnot
338 pursued. Mr.Ian LawsonDickofthepathologylaboratoriesinEdinburghfirstshowed
331 332
TTCMinutes5,(5March1934)TTCMinutes6,(28February1936)TTCMinutes 7,(11February1937),MRCFile1523/15. 337 STCMeeting,(28May1936),WF:STCS/G/50. 338 STCMeeting,(7October1936),WF:STCS/G/50. 339 E.B.Verney,AlfredJosephClarkObituaryNoticesofFellowsoftheRoyal Society 3(1941):969984.
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testsonSyntropan.TheurologistC.J.Bondhadalreadyperformedsomestudiesin dysuria.F.J.Barrington,anotherurologysurgeon,examinedthedrugintubercularcystitis,
341 asdidR.OgierWard,GeoffreyParker,JamesCarverandVictorDix.
340
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Edinburgh.Thiswasastimulantwiththesameactionasacetylcholineanditwasmarketed
344 345 inMay1935. BurroughsWellcomeproducedaversionofDorylinNovember1939.
Itisclearthatapartfromtheirinterestinhormonalextracts,foreigndrugsreceived limitedsupportfromtheTTC,untilthediscoveryofProntosilopenedthewayformore GermanandSwissdrugs,thoughseveralwereturneddown.Ironically,thedevelopmentof severalfurthersulphonamidesstimulatedfirmstohiretheirownmedicalstafftoestablish clinicaltrialsandthisnewpolicyledtophysiciansbeingtakenonbyAllen&Hanburys, GlaxoandMay&Baker,toarrangetheirownclinicaltrials. Howeverlackofclinicaltrialsdidnotalwaysstopforeigncompaniesfromreleasing theirproductshere,especiallyiftheyfellintothecategoryofvitaminsororganotherapies whentherewassufficientdataavailable.ForexampleMerckmarketedaliverextract Oroheptalin1937andHoffmannlaRochemarketedahistidinepreparationLorostidinfor ulcers. 8.8MRCStudiesofAntisera:LargeCooperativeTrialsandStatistics. WhilethepreviousaccountregardingnoveldrugsshowsthattheTTCseemedtobe satisfiedwithtestingafewpatients,theyalsoperformedstudieswithantisera,whichuntil 1935theTTCbelievedofferedbetterhopesofcombatinginfections.Twoexamplesare givenheretoshowthescopeofthestudies.Dr.MurrayLyoninEdinburgh,Prof. DavidsoninAberdeenandR.CruickshankandCowaninGlasgow,performedatrialof specificseraforpneumoniabetween1929and1934,whichLilienfeldascribedasthefirst collaborativestudy.346
344
TTCMinutes6,(28February1936)1523/15J.ChassarMoir,TheUseofDorylin PostOperativeandPostPartumRetentionofUrineLancet(30January1937):26163 J.S.Maxwell,TheTreatmentofPostOperativeRetentionofUrinewithDorylLancet (30January1937):26364Doryl(Merck)BritishMedicalJournal (11May1935):980 R.OgierWard,AcuteRetentionofUrineBritishMedicalJournal (21January1939): 12123SurgicalProcedureinGeneralPractice:ChronicRetentionofUrine British MedicalJournal (28January1939):17778. 345 STCMeeting,(29November1939),WF:STCS/G/50. 346 MRC1487,TTCTheSerumTreatmentofLobarPneumoniaBritishMedical Journal (10February1934):2415.TheSerumTreatmentofLobarPneumonia.AReport oftheTTCoftheMedicalResearchCouncilLancet(10February1934):29095A.M. Lilienfeld,CeterisParibustheEvolutionoftheClinicalTrialsBulletinoftheHistoryof Medicine56(1982):118 G.F.Petrie,andR.A.O'Brien.(twoletters)Treatmentof LobarPneumoniainAdultsBritishMedicalJournal (28March,1931):5578.
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However,fortheirownlargerserumstudies,theMRCadoptedadifferentapproach
347 tothatoftheTTC,andincludedinputfromthemedicalstatisticians,MajorGreenwood 348 andAustinBradfordHill. GreenwoodwasDirectoroftheMRCStatisticalUnitand
347
M.Greenwood,EpidemiologyanditsLessonsLancet (27January1934):201. GreenwoodwasanofficeroftheMinistryofHealthfrom1920,MRCMinutesII,(7July 1920):111. 348 BradfordHillwasonlyappointedtotheTTCatmeeting9on(14July1938),MRC File1523/15P.Armitage,BradfordHillandtheRandomizedControlledTrial, PharmaceuticalMedicine6(1992):2337R.Doll,SirAustinBradfordHillandthe ProgressofMedicalScienceBritishMedicalJournal 305(1926December1992):1521 6. 349 Theconferencetobeheldon27July1932wasreportedinTTCMinutes3,(8July 1932),MRCFile1523/15. 350 TTCMinutes5,(5March1934),MRCFile1523/15. 351 TTCMinutes5,(5March1934),MRCFile1523/15.
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O'BrienindependentlyarrangedforDrRichardArmstrong,abacteriologistat
352 CharingCrossHospital toteststaphylococcustoxoidincasesofbreastabscess,causing
confusionwhenArmstrongsenthisdataonincreasedantibodylevelstotheMRCand
353 askedforasmallgrant. IndoingthisOBrienupsettheMRCrulesonsoletesting
thestaphylococcaltoxoidsatpresentavailableinGreatBritainmaybeusefulforthe treatmentofboilsandstiesbuthavelittle,ifanyvalueforthetreatmentofsycosis
356 (follicularpustules,duetoinfectionbystaphylococcus). Therewasadifferenceof
opinionbetweenpathologistsanddermatologists,regardingfurunculosis(amoredeep
357 seatedinfectionofthehairfollicle). Theoverallconclusionwasthatthetoxoidhelpedin
treatingsuperficialskinlesions,butwasoflimitedvalueformoredeepseatedinfections, whichwerepronetorelapse.Asaresult,differentreportswererequestedforcarbuncles
358 whereitwaspromisingandfortoxaemia, whereasagroupofsixsurgeonsfoundit 359 notencouraging. Theseapparentlydiscrepantfindingswerediscussed,andthen
352
TTCMinutes6,(28February1936),MRCFile1523/15. L.E.H.Whitby,TheTreatmentofStaphylococcalSkinLesionswithToxoid Lancet(27June1936):145456R.Klaber,SpecificandNonspecificTreatmentofBoils, withSpecialReferencetotheResultsofTreatmentbyStaphylococcalToxoidLancet(3 October1936)78486R.S.Wale,K.Maddis,StaphylococcalToxoidintheTreatment ofDiabetesBritishJournalofComparativePathology 17(1936):279. 358 WilkiewasamemberofthecommitteeoftheMRC.In1938aUnitforClinical ResearchwasestablishedinEdinburghTTCMinutes6,(28February1936),MRCFile 1523/15. 359 TTCMinutes6,(28February1936),MRCFile1523/15F.H.K.GreentoT.R. Elliott,(28December1934),T.R.ElliottFiles,WIGC/42,TTC193334.
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FollowingarecommendationfromDaleandwiththebackingofboththe ChemotherapyandAnaestheticsCommitteesitwasdecidedtotestMercksbasalhypnotic,
361 trichloroethanol. Thishadbeenfoundtobedangerouslytoxicinastudyperformedat 362 St.GeorgesandatthePrinceofWalesHospital inTottenham. Dr.C.LangtonHewer,
wassuggestedthatWilliamEvansattheLondonHospitalcouldperformclinicalwork,as hehadrecentlydoneindependentworkonCoramineandothercardiacorrespiratory
360
C.LangtonHewer,DouglasBelfrage,TrichloroethanolonTrialLancet(3 December1938)12901.
363
TTCMinute9,(14July1938),MRCFile1523/15.
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supposethatforinternationalreasonsweshouldseektosupporttheFrenchCyclamideas againstCoramine.ButIamnoteagertodomuchforthesecontinentalfirmsunlessthey
367 haveverypromisingsubstancestooffer.
TheCommitteediscussedcompoundsfromOrganon,ParkeDavis,Merck, BurroughsWellcome,BDHandBoots,MayandBakerandCilag) 8.9ConclusionsRegardingtheTherapeuticTrialsCommittee. TheTTCwasestablishedagainstabackgroundofincreasinggovernment interventionindrugproductionandawaveofprotectionismbroughtaboutbytheharsh economicclimate.Bytheendof1939theTTChadperformedstudiesonover60drugs.I haveattemptedtogiveaflavouroftheoverallstudiesandalthoughIrecognisethatthisis inevitablyincomplete,theimportantpointistogetanoverallimpressionofthetypeand scopeofstudiesperformed.Thestudiesshouldbejudgedonthemeritsoftheresearchat thetime,notaccordingtowhichdrugsgavethelastingbenefits:insulin,sulphonamidesand steroids.Itwasacomplexprocesstounravelthetestingofallofthedrugsandfurther supportivedatacouldbefound,buttheworkdonesofargavemeaninsightintothe researchandstrategiesofBritishpharmaceuticalmanufacturersintheinterwarperiod.
365
T.R.ElliotttoF.H.K.Green(29June1938):T.R.ElliottfilesWIGC/42,TTC 193542.
368
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Certainoveralltrendsarediscernable.Firstly,severalBritishfirmshadabacklogof compoundsreadytobeassessedin1931whentheTTCwasestablished.TheTTCclearly setouttheirstallnottoevaluateGermandrugsandtoassistBritishmanufacturers whereverpossible,andthemajorityofdrugstestedupto1935wereBritishuntilProntosil changedthewholeapproach.Ontheotherhand,organotherapiesfrombothSwitzerland andHollandwereevaluatedinthehopeofbringingsomeordertotheveryvaried preparationsonsale.Butonseveraloccasionswhenorganotherapieswereavailablefrom foreignmanufacturers,theTTCstillwentaheadtotestandencouragethereleaseofa Britishversion.TheMRCperformedclinicaltrials,primarilyinthosecentreswherethey hadalreadyfundedresearch.Thismeantthatalargeproportionofstudieswereperformed atUCH,St.BartsandGuysinLondon,butalsoinEdinburgh,Glasgow,Manchester, SheffieldandOxford,withthesametrialistsnamesappearingseveraltimes. TheformersecretaryoftheTTC,F.H.K.Greennicelysummarisedthe requirementsandtheachievementsoftheTTCintwopapers.Inonepaperheconfirmed thedifficultiesfacedbyBritishmanufacturersowingtoacertainreluctanceofmany Britishdoctorstocarryoutclinicaltrialsatthedirectrequestofcommercialfirms,and especiallytoallowtheirnamestobequotedastheauthorsofsuchtestsandthisplaced BritishmanufacturersatadisadvantagecomparedwithsomeoftheirEuropean
369 competitors.
Certaintrendsalsoappearinthetypesofdrugassessed,withaprolongedfocuson organotherapy.TheneedsoftheTTCandthecompanieswerecomplementary,becauseof thecloseinvolvementoftheMRCinbiologicalstandardisation.Asaresult,theweaker biologicalswereweededout,andthemoreconcentratedversionsallowedMRCstaffand universitychemiststoelaboratethestructuresandtosynthesisetheactiveingredients, whichcouldinturnbestandardised.Aconsequencewithlonglastingconsequencesforthe pharmaceuticalindustryisthatmanycompaniessimultaneouslyjumpedontothe bandwagonandpreparedsyntheticderivativesofeachnewdrug.Nowherewasthis clearerthanintheexamplegivenoforganotherapy,whentherewereseveralpreparations ofOestrinandProgestinandsuprarenalcorticalextract.In1935,justfiveyearslaterthe samesituationarosewhensulphonamideswerediscoveredinGermany,butFrench workersshowedthatthepatentswereinvalid,astheactiveingredienthadbeenidentified
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By1934collaborationswereincreasinglycommonbuttherelationshipofscientists anddoctorstocommercewasproblematical.Dale,inhisRoyalSocietyrolereceiveda letterfromElliottdiscussingaProf.(Kapitza)whoaskedtoreceivefeesforsecretwork withbusinessfirms.Elliottraisedthepossibilityofdeflectiontoshorttermaimsandasked Dalethetheoreticalquestion: WouldyouallowLaidlawtotakecomfortablefeesfromWellcomeforadvice onpreparationofdistempervirus?WhynothaveMellanbyhavegivenhis adviceandevenhispowerfulnametoGlaxoLtd.inthepreparationoftheir 370 patentcoveredvitamineDandbeensuitablyrecompensated.
ElliottreferredtotheAlistofRoyalSocietymenandexpressedconcernattheimpartial
371 positionoftheSocietyinitsincreasingrolewithindustry. AccordingtoGreentheTTC
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marketinBritainorabroad.Greenlistedthemostimportantagentslaunchedbythe
376 committeeascalciferol,digoxin,Prontosil,stilboestrolandSulphanilamide.
hewrotethat:itwasearlyrealisedthatthemedicalstatisticianisavaluablememberofthe planningteam,evenwhenthenatureoftheinvestigationisnotsuchastorequirelarge
373 374
TheInvestigationofNewDrugs,PharmaceuticalJournal (1June1935):653. ACentralLaboratory,PharmaceuticalJournal (1June1935):653. 375 F.H.K.Green,ClinicalEvaluationofRemediesinBritain,Brit.Med.Bull.2 (1944):5860. 376 F.H.K.Green,TheClinicalEvaluationofRemediesTheLancet(27November 1954):10851091.F.H.K.Green,Brit.Med.Bull (1944)2:5860L.Colebrook,A.W. Purdie,Lancet(1937):1237,1291W.R.Snodgrass,T.Anderson,BritishMedicalJournal (11December1937)II:1156. 377 F.H.K.Green,ClinicalEvaluationofRemediesinBritain,Brit.Med.Bull.2 (1944):5860.
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andhowthiswasovercomebytheorganisationofblindedtestsandtheuseofinert substances.Unfortunatelythereisnodatainthefilesorpublicationstosupportsuch statements.ThestudiesarrangedbytheTTC,generallyemployedseveralcentres,but recruitedrelativelyfewpatients.Thedesignofthestudiesallowedthemtoreadilyidentify overtlytoxicdrugsordrugsthatsimplydidnotworkorwerepoorlytolerated.Wherethey struggledwaswiththemanydrugsbeingproducedbydifferentfirmsthatwerevariantsor marginalimprovementsonathemethosethatwerebetterextractsorsyntheticversions orimprovedsalts.Thiswasparticularlyproblematicwhenthedrugwastestedinan unusualandrarediseasesuchasmyastheniagravis.Despitetheclaimsoftheroleof statisticians,Ifoundnoevidenceandthenumbersrequiredwerenotplanned,ratherthe TTCarrangedforasmanypatientstobetreatedascouldbemustered. Theimpressionisgiventhattheevaluationofmedicineswasbasedona combinationofthescientificrationale,thedatapresentedfromanimalstudies,thepurity ofthedrugsandfreedomfromothercontaminantsandfinallytheclinicalefficacyand toleranceinclinicaltrials.InadditionfactorssuchastheavailabilityofaBritishversionand tosomeextentcostswerealsotakenintoconsideration.
Whataboutfromthemanufacturerspointofview.Asidefromthedisappointmentof theslowprogressofsomestudies,firmswerefrustratedbythelackofcontrolovertheir productsdestiny,andtheirlackofaccesstocliniciansbutasRutherfordHillpointedout therewasnothingtostopthemplacingproductsonthemarket.Attheendof1937J.W. TrevangaveanoutspokenPresidentialaddressonthissubjecttotheSectionof TherapeuticsandPharmacologyoftheRoyalSocietyofMedicine.Herecalledhowthe spateofsyntheticdrugshadbeguninthe1880s.Heannouncedthatsomeresponseshad beenlessdramaticthanhopedfor.Hereasonedthat: Ifaphysicianispreparedtotaketheriskofadministeringanewproductto aseriesofpatientsheshouldbepreparedtotaketheriskofwithholdingthe
378
F.H.K.GreenTheClinicalEvaluationofRemediesLancet(27November1954):
1088.
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remedyinthecaseofsomepatientsuntilacertainprobabilitywas 379 established,greaterthansaytentoone,thatthematerialwasactive. HegaveexamplessuchastheuseofvitaminAforinfectionsandvitaminBfor constipationbasedonlittleevidence.Hereferredtothefactthatduetothehappyhunting groundofthesyntheticchemist,chemotherapywasnowoneofthechiefgrowingpointsof therapeuticsandmedicalmenmightlookforwardtoaconsiderablyenlargeddailypost. Hecomplainedaboutthereprehensiblepracticeofmakingstatements,whichwere demonstrablyuntrue,althoughmadewithapparentscientificassuranceandhethoughtthe rubbishoutweighedthegoodandhewaspessimisticaboutheadingtowardsatherapeutic darkage.Themoneyspentwasenormous,soclearlytheadvertisementshadsomeeffect. Trevanhadreviewed43recentcasesandfoundthatevenbylenientstandardsonly27 claimedfoundationinthelaboratoryorclinicandthat13weremisleadingorsimplysilly. HefeltthatonesolutionwouldbetohaveanindependentlaboratoryattheLondonSchool ofHygieneandTropicalMedicineoratthePharmaceuticalSociety.Oneoftheproblemsof competitionwasthemultiplicationofsimilarproductsbycompetingmanufacturersandthis couldnotbeavoidedaslongasproductionwasinprivatehands. HedidcommentoftheTTCthattheywere:doingextremelyvaluableworkandofwhich hewishedthemanufacturerswouldmakemoreuse.Coulditbehopedthatnonewremedy
380 wouldbeintroduceduntilithadbeenpassedbysuchacommittee.
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Patulinwasanaturalextractderivedafungusthatgrewonapples.Thislatterstudywasthe brainchildofPhillipDArcyHart,DirectoroftuberculosisworkfortheMRC,whowasto
385 beintimatelyinvolvedinthe1946,randomisedcontrolledstudyofstreptomycin. Cox 386 MaksimovsummarisedherinterpretationthattheTTCbecamearegularmachine. She
381
MRCMinutesIII,(25October1929):167(16May1930):84(28November 1930):175(23October1931):127(21October1932):171. 384 H.Raistrick,PatulinintheCommonCold:CollaborativeResearchonaDerivative ofPenicilliumpatulumbainierLancet(20November1943):625. 385 P.DArcyHart,AChangeinScientificApproach:fromAlternationtoRandomized AllocationinClinicalTrialsinthe1940sBritishMedicalJournal (28August1999):319 386 D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945. Expertise,theStateandthePublic(Cambridge:PhDthesis,September1997):185.
387
417
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ofFisherinteractingwiththeTTCandthismeantthathisexpertisewasnotutilisedin
389 ordertotranslatehispowerfulideasonexperimentaldesignintoaclinicalcontext.
Hillandothers,Fisherplayednopartinthedesignofclinicaltrials. Theinterwarperiodshowsanincreasingsophisticationof drugsandthemeansof assessingthem.Liebenauagreedthat: Asdrugcompaniesrequiredincreasinglytechnicallyadvancedpeoplefor researchanddevelopment,andasmedicalscientistswereincreasingly availableforindustrialemploymentduringtheinterwarperiod,theuseof 393 newsciencebecamethecentralelementofcompetition. ThereluctanceoftheBritishmedicalprofessiontocollaboratewithindustryintestingtheir newdrugsstifledBritishresearchinsyntheticdrugsuntiltheMRCassistedattherequest ofindustryinestablishingtheTherapeuticTrialsCommitteein1931.Ihaveexaminedthe successorotherwiseofthisventure.ItwashelpfulinthoseareasintheMRCcomfortzone wheretheycouldassistingettingaBritishversionofadrugonthemarket.Theyhad greatersuccessintestingsomebutnotallorganotherapiesandotherdrugsthatcouldalso betestedbybiologicalstandardisationorthesuccessofwhichcouldbefollowedinthe
389 390
J.AustokerandL.Bryder,inJ.AustokerandL.Bryder(eds.),(1989):47. PersonalcorrespondencebyletterwithSirAustinBradfordHill.(6October1988) andtelephonediscussion(1January1989). 391 A.B.Hill,SerumTreatmentofPneumonia(22December1933),MRCFile1487. 392 A.B.Hill,PrinciplesofMedicalStatisticsseriesofarticlesTheLancet(1937) 393 J.Liebenau,ResearchandDevelopmentinPharmaceuticalFirmsintheEarly TwentiethCenturyBusinessHistory 26(1984):329346.
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Anotherreasonforinsulinnotbeingagoodmodelforclinicaltrialswasthatthe firmshadtointeractwithphysiciansthroughtheMRCandwerenotallowedindependent studies.ItwasonlyafterthediscoveryofProntosil,andthepreparationofsulphonamides bymanyBritishfirmsthattheirsyntheticdrugswereindemand. TheTTCdealtwithabacklogofdrugsthathadnotbeentested,givingclear prioritytoBritishdrugs.Ithelpedtoestablishanetworkofclinicalresearchcentresand contributedtowardsthestandardisationofdrugs.Italsoofferedanindependentbodyof opiniononnoveldrugsandmethodsoftreatment,keepingdoctorsfreeofdirect collaborationwithindustry.TheTTCwasmostsuccessfulindealingwithbiologicaldrugs, largelybecausethatwasanareawheretheMRCwerecomfortableandhadconsiderable expertise. ThisthesisdoesnotextendintoandbeyondtheSecondWar.Howeveritisclear thatBritishfirmscameoutevenstrongerhavingbeeninvolvedinthedevelopmentofboth penicillinandtheantimalarials.Theformerwasagainunpatentedandofferedfurtherscope forchemicalmanipulation.SuchwerethebenefitsofantibioticsthatthelargerBritishfirms didnotseetheneedtocollaboratewiththeTTCpostwaralthoughthesmallerfirmNapp did.Indeedironically,givenitsinitialraisondtreoftheTTCitbecameameansfor foreigncompaniesespeciallyfromHollandandSwitzerlandtohavetheirdrugstested. Britishfirmsinsteadbegantoestablishtheirownstudies.Thistrendhadbegunin1936 whenMay&BakerappointedthephysicianRobertForgantoestablishclinicaltrialsof M&B693andtoanswermedicalqueries.GlaxohadtheirownphysicianinDrHector
394
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395
EricScowenvisitedICIinJune1990.Personalcommunication.Healsoevaluated Progestininpatientswithchronicinterstitialmastitis,TTCMinutes7(11February1937): 5.
420
ConcludingComments CHAPTER9:ConcludingComments.
421
Thischapteraimstobringtogetherasummaryoftheresearchperformed,thebroad trendsdiscoveredandsomeprovisionalconclusions.Italsoidentifiesareaswherefuture researchersmayprofitablyextendthisstudy. FollowingtheintroductorychapterinwhichIexaminedthehistoriographyofthe pharmaceuticalindustryandclinicaltrials,IdemonstratedinChapter2,theextentofthe relianceonGermanyforsyntheticdrugsandchemicalintermediates,andthesmall capacityofBritishpharmaceuticalfirmsincomparison.Britishpharmaceuticalfirms facedaparticularshortageofchemistswithpracticalskillsofchemicalengineeringand drugproduction.ThegovernmenthadfailedtosupportthecompetitivenessofBritish industryinitspatentlaws,andwithitshighdutyonalcohol,andfocussedinsteadonthe battleagainstpatentmedicines.IncontrasttotheesteeminwhichtheGermanindustry washeld,thatinBritainhadapoorimage,contributingtothedifficultyingettingdrugs testedinBritainincontrasttotheclosecollaborationsbetweenindustryandacademiain Germany.TheimpressioninBritainwasthatitwaseasyforGermanfirmstogettheir newdrugstested. IntheremainderofthethesisIhaveaddressedthesepoints,firstlytoexplainhow Britishfirmswereabletomakesyntheticdrugsandthenhowtheyremainedcompetitive. InChapter3,IdemonstratedhowBurroughsWellcomebecameaninnovativecompany, continuallystrivingtoproducedifferentiateddrugs,takingideasfromotherinnovators suchasParkeDavisandGermanfirms.BurroughsWellcomecuttheirtieswithWyethto establishtheirownmanufacturingfacilities,andemployedGermanengineerstobuildand runtheirchemicalmanufacturingsite.HenryWellcomeestablishedChemicaland PhysiologicalLaboratoriesthatcollaboratedclosely.Theirstrategywassetoutearly, combiningadvancedAmericantablettingtechnologywithnoveldrugsfromGermanyand combiningGermanstylepatentingandtradenameswithAmericanstyleselling techniquesemployingsalesrepresentatives. HenryWellcomeemployedthemostpromisingresearchersoftheera,throughhis contactsinCambridgeandLondon.TheappointmentsofBarger,DaleandGlennywere inspiredchoicesthathavebeenwelldocumented,butIhaveemphasisedtheimportanceof chemistssuchasFrederickPower,whohadauniquecombinationofexperienceresulting fromworkinpharmacies,trainingatthePhiladelphiaCollegeofPharmacy,andresearch atimportantGermanandSwisslaboratories.Ialsoemphasisethebenefitsoftheclose 421
422
Thephysiologicalresearchperformedinthelaboratoriesunderanimallicensesis wellknownthankstoTansey,butIhaveshownthatsyntheticchemistrywasafarmore importantandearlierfeaturethanhaspreviouslybeendescribed,beginningsoonafterthe arrivalofPowerandJowettin1896. TheTabloidnameatBurroughsWellcomesignifiedknownpurityandstrength, achievedbyemployingexpertbotanistsandchemiststodefinethespeciesofplants,to standardiseextracts,andtodeterminethechemicalstructuresofpurifiedalkaloidsand glycosides,whichwerethenassayedphysiologicallyagainstpuresynthesisedchemical standards.Someactiveingredientswerechemicallymodifiedtoevaluatetherelationship ofchemicalstructuretobiologicalfunction.Potencywasmeasuredbythecontentof specificalkaloids,ratherthantotalalkaloids,andthisgavecompetitiveadvantagesover firmswithoutlaboratories.Syntheticchemistryalsocontributedtothepreparationofsalts ofnaturalproductstomakethem moresolubleorstable.Furtherdifferentiationwas achievedbyincorporatingGermansyntheticdrugsintoTabloids,andfrom1906by incorporatingopticalisomersofsomedrugs,suchastropeinesandhyoscyamine, increasingpotencydramatically.Somenaturalmoleculeshadchemicalstructuresthat
1 existedinamixtureintwoormoremirrorimageforms(oneforeachchiral centreintheir
chemicalstructure)Jowettandhisteamdiscoveredhowtoseparatethese,andhowto preparechemicalsinonlythebiologicallyactiveform. PowercontributedtothePharmacopoeiaandCodex,andensuredthatthehighest possiblestandardswereset,sothatfewerfirmscouldachievethosetargetsandtherefore fewcouldcompete.BurroughsWellcomesoldafewsyntheticdrugsincludingthe arsenical,Kharsin,someisoquinolinesandsyntheticSuprarenin,butthesewereminor comparedtotheirthrivingTabloidalkaloidbusiness.Theydidnoteventrytocompete withGermanyinpreparingthepopularsalicylatesorothersyntheticdrugsevenwhenthey werebeyondtheperiodofpatentprotection.Theimportanceofsyntheticchemistryat BurroughsWellcomefrom1896,andtheparalleldevelopmentofanunderstandingof chemicalengineeringprinciplesattheWorks,helpstoexplainhowBurroughsWellcome
1
ConcludingComments wereinapositiontopreparecomplexGermansyntheticdrugswithinweeksofthe
2 outbreakoftheFirstWorldWar.
423
Chapter4assessedthegeneralimpactoftheFirstWorldWarontheBritish
3 PharmaceuticalIndustry. AlthoughtheextentofthedependenceonGermanywaswell
recognised,thespecificquantitiesofeachdrugandchemicalintermediatesrequiredwere verypoorlyunderstoodattheoutbreakofthewar,asBoardofTradefigureswerenot specificordetailedenough.Thesituationwascomplicatedbytheneedforchemical intermediatesandespeciallyasthesameintermediateswererequiredfortheproductionof dyesandexplosives,socentralcoordinationwasessential,andaMinistryofSupplieswas created. Idemonstratedhowvariouscommitteeswereestablishedtodecidewhichdrugs wereessentialtoassesswhichcompaniesmadeorcouldmakethem,wheretheshortages were,andwhatwasneededtopreparetheGermandrugs.Furthercommitteesorganised suppliesofessentialchemicalintermediates.Pharmaceuticalmanufacturerswere representedonallofthesecommittees,includingtheindividualsHoward,Tyrer,Hill, Morson,Lescher,WebbandJowett. Immediatelegislationpreventedtheexportofessentialmaterials,whileGerman patentsofsyntheticdrugswereabrogatedalongwiththeirTradeMarkstoencourage manufactureinBritain.Severalcompanieseventuallyproducedthelesscomplexsynthetic drugs,buttheysoughtassurancesthattheireffortswouldberewardedbyprotection againstGermancompetitionpostwar,beforetheyinvestedheavilyinmanufacturing facilities,whichformedthebasisofastrongerindustrypostwar. Beforethewar,GermanSalvarsanhadbeenstandardisedandtestedforpurityby EhrlichinFrankfurt,sotheMRCtookoverthisroleinBritainduringthewar.Ihave demonstratedbyreferencetotheSalvarsancommitteehowthepreviousBurroughs Wellcomeworkonbiologicalstandardisationwasinfluential.DaleandEwinsanda stringofexBurroughsWellcomestaffsupportedtheirformercolleagues,andlaterMay& Baker,bydemonstratingthatBritishSalvarsanwasasgoodandsafeastheGerman version,bycollatingdatafromhospitalsathomeandinFrance.However,theirexternal
2
423
ConcludingComments supportforBritishdrugsmaskedpoorlyrecordeddatathattheyhadlittlecontrolover.
424
Duringthewinterof191415,afterPowerleftBurroughsWellcometoreturnto America,FrancisCarrledafurtherexodusofstafftojoinrivalsBoots,wherehe establishedsyntheticdrugmanufacture,extendedtheirlaboratories,andprepared salicylates,anaestheticsandantiseptics,butalsoabsorbentmaterialsforgasmasks.The governmentencouragedthesupplyofchemicalintermediatestocompaniesin1915by establishingBritishDyestuffs,andthemergerofseveralfirmstoformDistillersprovided plentifulalcohol.TheestablishmentoftheDepartmentofScientificandIndustrial Researchin1915providedfurtherchemicalintermediatesandencouragedcollaboration withindustry.Carrandotherpharmaceuticalmanufacturerstookanactiveroleinthe establishmentoftheAssociationofBritishManufacturersin1916,whichledtoabetter bargainingpositionforBritishPharmaceuticalmanufacturersinthecampaignforlonger termprotectionhewasamemberoftheirfinechemicalcommitteealongwithHilland Howard. IemphasisedthegrowingimportanceofFrancisCarr,whowasrewardedwitha CBEforhiswartimedrugmanufacturingatBoots,andwaschosentorepresenthis country,alongwithIvanLevinstein,onABCMvisitstotheGermanfactorieswithinthe occupiedterritories.FrancisCarrwasthenheadhuntedtojoinCharlesHillatBritish DrugHousesin1920,withthepromiseofmajorfundingtocreateanextensive manufacturingbusinessandhisloyalteamfollowedhim.Ishowedhowattheendofthe warBurroughsWellcomelostseveralfurtherexperiencedstaff,includingFrankTutinand HaroldKing,whojoinedDaleattheMRC.FrankPymanleftforManchesterUniversity,
4
P.Hartley,InternationalBiologicalStandards:ProspectandRetrospect Proc.Royal
424
ConcludingComments
425
beingreplacedbyThomasHenry,whospecialisedinalkaloids.Thesestafflossesmay haveinfluencedsomeoftheirpolicydecisionsregardingwhethertofocusonsyntheticsor traditionaldrugs. Theperiodfrom1919to1931wasdealtwithin3parallelchapters(57),dealing withpostwarmarkets,howeachfirmrespondedandnewlegislationondrugs,howthe ABCMcampaignedtotheMRCforasystemofclinicaltrials,andthestrategiesfor productdevelopment,describedbytheBurroughsWelcomeScientificandTechnical Committee.Muchofthisrelatedtotherecognitionthatastrongindustrywasneededin BritainforstrategicreasonsandrequirednurturingandIdemonstratedseveralwaysin whichprotectionfortheBritishpharmaceuticalindustrywasachieved.TheTradingwith theEnemyActandtariffsondyeimportswereextendedtopharmaceuticalsinFebruary 1919.Withexportmarketsreopened,therewasahoneymoonperiodoftrading,butthe SankeyjudgementinDecember1919ledtoafloodingofthemarketwithGerman products.TogetherwithGermanreparations,andadownturnintheeconomy,thisledto overcapacityonceagaintheindustrywasunderthreat.Carrcampaignedforfurther protectionandresearchtoprotectthecountryagainstfutureattack,whilePearsonof BurroughsWellcomepromisedthatasyntheticdrugindustrycouldbedevelopedin Britain iffirmswereallowedaperiodofprotection. Idemonstratedthatin1922theABCM,representingthepharmaceuticalindustry, approachedtheMRCforasystemwherebynoveldrugscouldbeevaluatedinclinical trials.Previoushistoricalwork,originatingfromLiebenau,suggeststhattheMRC imposedamethodoftestingofnewdrugs.All Britishfirmshaddifficultyarranging studiesofnovelproducts,andBurroughsWellcomeonlyhadsuccessfulclinicaltrialswith theirtropicalmedicines,evaluatedoverseas.TheTrialsCommitteedidnotmaterialise immediately,astheMRCbecameengrossedwithinsulin,collaboratingwithseveral Britishfirmstoprepareinsulinonalargescale,andtoorganiseclinicalstudiesofinsulin. However,followingexploratorystudiesbytheMRC,itwasFrancisCarratBDHwho perfectedtheproductionofinsulin,suchthatwithinayearBDHproduced95%ofthe materialrequiredforBritishuse,thusmakingtheclinicaltrialspossible.Productionof insulinwasahighlytechnicallargescaleoperationthatrequiredsignificantmodification ofexistingmanufacturingplant.In1924Carrachievedsimilarsuccessinthelargescale productionofthepreviouslyprohibitivelyexpensivehormone,thyroxineandBritainheld
Coll.Med.38(1945):45. 425
ConcludingComments
426
aleadingpositioninproductionofthenewhormones.In1925theTherapeuticSubstances Actwaspassed,makingitcompulsorytohavebiologicalsevaluatedbeforesale,and formalisingtheMRCroleinbiologicalstandardisation aroleitwillberecalledthatwas initiallydevelopedwithinBurroughsWellcome.Asaresultsomeforeigndrugswere excludedfromtheBritishmarket.TheABCMapproachedtheMRCagainin1926fora systemofclinicaltesting,buttheMRCinsteadestablishedaChemotherapyCommittee, whichaimedtoevaluatenovelchemotherapeuticagents,baseduponthesuccessofanew Germandrugactiveagainsttrypanosomalinfections,Bayer205.TheDSIRweremeantto developnovelchemotherapeuticagents,andweregranted30,000toassistthisprocess andtheyapproachedBurroughsWellcomewithanofferofcollaborationbutthefirms ScientificandTechnicalCommittee(STC)dismissedtherequest,insistingthatthemain collaborationneededwasinestablishingclinicaltrialsoftheirnewowndrugs. JowettsetdownguidelinesfortestingofnovelproductsatBurroughsWellcome, andthecriteriaforbringingthemtomarket.HebemoanedthefactthatBurroughs WellcomehadfallenbehindbothBootsandBritishDrugHouses,andheputtheblame firmlyontheshouldersofFrancisCarrandhisexternalpoliticalinfluence.Burroughs Wellcomewasinsularbycontrast,andhavinglostsomanystaff,theyrarelyallowed employeestoattendexternalmeetings,forfearofmorepoaching.Idemonstratedhow Carrestablishedhimselfasadrivingforceforchemicalengineering,buthealsowas PresidentoftheSocietyoftheChemicalIndustry19267,givinghimtheplatformto describehisvisionofthefuturesyntheticpharmaceuticalindustry,andtheneedforan organisedsystemofclinicaltrialsfordrugsproducedbyindustry. TheMRCfinallygotthemessageandcreatedtheTherapeuticTrialsCommittee (TTC)in1931,afterafurtherpushfromtheABCMinvolvingHill,Carr,Pearsonand Gamble.Britishdoctorsremainedreluctanttocollaboratewithpharmaceuticalfirms despitetheirgrowingcommitmenttolaboratoryscience,andthefewwhodidworkwere notpreparedtoputtheirnamestopublicationssupportingnewdrugs.ThisplacedBritish firmsatacompetitivedisadvantage.WhereasdoctorsinGermanywereusedtotesting noveldrugs,thiswasnotthecaseinBritain.PrevioushistoricalresearchonSalvarsanand insulinhasnotaddressedthisissueasthesedrugswerealreadyrecognisedassignificant advancesfollowingstudiesoverseas,anddoctorswerekeentoobtainsupplies.Thequite differentchallengeforBritishfirmswastosecureclinicaltestingoftheirownnoveldrugs, especiallytheirearlyattemptsatmakingsyntheticdrugs.
426
ConcludingComments
427
AlthoughtheTTCproposedrestrictingtheirservicetonoveldrugs,theyoftentook theopportunitytotrialan Englishversion,eveniftherewasalreadyaforeignversionof adrugonthemarket.TheygavepreferencetoBritishdrugsandturnedawayseveral foreigndrugsuntilonecamealongthatwastoogoodtoignore ProntosilfromBayer. TheTTCwasmostsuccessfulintheirareasofspecialinterestsuchasorganotherapy,and IagreewiththeconclusionofValier,whoexaminedstudiesoflivertherapyinpernicious anaemia,thattheMRCweremostcomfortablefollowingprogressinthelaboratoryrather thanatthebedside.Severaloftheirstudieswerefailures,notonlybecauseofpoorresults, butoftensimplyduetopoorrecruitmentofpatients.Theanalysisofallofthestudiesleft mewithquiteadifferentimpressioncomparedtothereflectionsoftheTTCsSecretary,
5 FrankGreen,whosummarisedthemajorstudies. HefocusedontheTTCsuccesses,most
ofwhichoccurredinthelateryears,andoftenasaresultofimprovedformulationsof extractsandtheprovisionofsynthetichormonesandvitamins. IhaveexaminedtheTTCfromtheperspectiveofthepharmaceuticalfirmsaswell asfromtheMRCside.TheMRCrepackagedtheTTCasbeingtheirowncreationanda focusfordevelopingnoveldrugs,andyetIhaveshownthatitwasonlyestablishedafter repeatedattemptsbytheABCMin1922,1926and19301,anddidnotonlyexamine noveldrugs.ThemostfrustratingaspectforBritishpharmaceuticalfirmswasthatfirms werenotallowedtocontactcliniciansdirectly.ValierdescribedhowtheMRCfrowned uponJohnWilkinsonofManchesterintheperniciousanaemiastudy,whenhe collaborateddirectlywithBoots.InotedsimilarexampleswhenOBrienofBurroughs Wellcomeestablishedhisowntrials,andwhenBurroughsWellcomewasaskednotto establishparalleltrialsofergotoxineinGermany.Idiscoveredthatseveralfirmsgot aroundthisinthelater1930sbyemployingtheirownphysicianstoliaisewithdoctors, oncetheyhadestablishedasuccessfulproduct.Glaxo,Allen&HanburysandMay& Bakerallemployedtheirownphysicianstoanswermedicalqueries,butalsotoestablish clinicaltrials.Thistrendcontinuedintothepostwarperiod,untilinthemid1950sthere wereenoughphysiciansworkinginindustrytocreatetheirownAssociationofMedical
427
428
materialIhadalready,IconcludedthisthesisattheoutbreakoftheSecondWorldWar. Anextensionofthisworkintothepostwarperiodwillfollow. WemaynotethatBritainonlygainedaninsightintotheclinicaltrialsoperationsof GermanfirmsaftertheSecondWorldWar,andafurthervisittoGermanfactories,this timebytheCombinedIntelligenceObjectivesSubcommittee.Ithadbeenwrongly assumedthatsomesortofcentralisedclinicaltestingprocedureexisted.Representatives ofthemaincompaniesincludingMay&Baker,BurroughsWellcome,GlaxoandICI foundthatBayerhadaScientificDirectorofPublicityintheperiod192335,witha departmentsplitintotwosectionsforarrangingclinicaltrialsandforsalespropaganda.In thefirstsectiontherewere5physicianscoveringbothgeneralandtropicalmedicine. FirmshadtoorganisetheirowntestsandIGFarbenweregiven34yearsbeforedrugs wereputonthemarket.Initialtrialswerefirstcarriedoutby14clinicians,andthenwere broadenediftheproductlookedpromising.Lessthan5%ofdrugstestedstayedthecourse andwereissuedcommercially,followinganapplicationtothegovernment.Inthesales departmentatBayertherewere70doctorsqualifiedinbiology,pharmacologyand chemistryandtheyweredividedtocovertheregionsofGermany.Therapeutische Berichte(TherapeuticReports)wassentoutmonthlyto70,000doctors,andaphysicians
7 yearbookwasalsoprovided.
ThisbecametheBritishAssociationofPharmaceuticalPhysicians,andin1976,The SocietyforPharmaceuticalMedicinetoreflecttheexpansionoftherole.AFacultyof PharmaceuticalMedicine,affiliatedtotheRoyalSocietyofMedicinewasestablishedin October1989T.B.Binns,WhatdoPharmaceuticalPhysiciansActuallyDo? PharmaceuticalMedicine1(1986):213219P.D.Stonier,DiscoveringNewMedicines: CareersinPharmaceuticalResearchandDevelopment(Chichester:J.Wiley,1994)D.M. Burley,T.B.Binns(eds.)withaforewordbySirAbrahamGoldberg,Pharmaceutical Medicine(London:EdwardArnold,1995)F.J.Gabbay,A.J.Salter,TheSocietyof PharmaceuticalMedicineDevelopmentoftheDiscipline,J.Pharm.Med.1(1991):53 60. 7 IGFarben:ThePropagandaDepartmentPharmaceuticalJournal (2March 1946): 137. 428
ConcludingComments
429
Mygeneralconclusionisofgradualprogressbeingmadeby Britishpharmaceutical firms.TheyhadendedtheFirstWorldWarcallingforprotectionsothattheycould establishasyntheticdrugindustrytocompetewithGermany.Thiswasalwaysgoingto taketime,sotheyevaluatedthemanyotheropportunitiesthatcametheirway,andwere successfulinproducingenoughinsulin,thyroxinandvariousorganotherapypreparations andvitamins,whichsatisfiedthehomemarketandalsogeneratedexportsales.Whereas previousauthorshavetakeninsulinasamodelforthedevelopmentofclinicaltrials,little attentionhasbeengiventothecomplexitiesofmanufacture.Ihavepointedoutthescaling upofplantrequired,thenewcentrifugalfiltrationprocedures,therefrigerationofthe variousprocessesandtheneedforcarefulcontrolofacidconcentration.Therewere similarproblemsintheproductionofotherhormonesandtechniqueshadtobedeveloped forcontinuouslowtemperatureevaporationsandforretrievingthevastquantitiesof
9 alcoholusedasasolvent. ThesamewastrueforvitaminsandFrancisCarrovercame
manyofthesedifficultiesatBDH,includingthecomplexsterilemanufactureplacinghis firminagoodpositionforsimilarworkonfurtherhormones,vitamins,andultimately
10 antibacterials. HaditnotbeenforthesedevelopmentsBritishfirmswouldnothavebeen
M.RobsonTheBritishPharmaceuticalIndustryintheFirstWorldWarinJ. Liebenau(ed.),(1988):82105.
9
ConcludingComments
430
11 manufacturedartificially. Inorderwords,thepatternheforesawwasagradualswitch
littleemphasisonR&D.Hewrote:toproduceinsulintheyhiredCarr,whereasI clearlyshowedthatBDHhiredCarrin1920,andwerepreparedtoinvest250,000before insulinwasevendiscovered.LiebenauwrotethatBootshadanalystsonly,butthiswas notthecaseitseemsthathemeasuredBritishfirmsonlyagainsttheGermanmodelofa largelaboratorystaff,searchingformanyyearsfornoveldrugssuchasSalvarsanora Bayer205.GermanfirmssuchasHoechstandBayercouldaffordtoindulgethismodel astheyhadtheinfrastructure,includingsuppliesofintermediatesandprofitsfromthedye businessandalsobenefitedfromhighsalesofmanyoftheearlysyntheticdrugssuchas phenacetinandaspirin.TheBritishindustryincontrastwasopportunisticintheinterwar period,butitcouldbearguedthatthiswasanefficientuseofthelimitedresources, tailoringtheireffortstoidentifyopportunitiesthathadalreadycomeoutofpatent modifyingpatenteddrugsandcollaboratingwithexternalinventors,asGlaxodidwith Steenbock. Suchhistoricaljudgementsbegthequestion,whatisresearchanddevelopment? Doesresearchnotalsoincludefindingbetterdrugs,purerdrugs,preparingthosewith greatersolubilityandlowersideeffects,andparticularlywastheworkdonebyBurroughs Wellcometoidentifyandstandardisetheactiveingredientsoftheirdrugsnotresearch?It certainlyledtotheidentificationofnovelactivedrugs.Developmentincludesidentifying methodstoassessthesafetyofdrugsinpreclinicalmodelsandimprovingtheproduction andreliabilityofthemanufacturing,asCarrsooftendid.Myargumentisthatbythese standardsofresearchanddevelopmenttheBritishindustrywassuccessfulintheinterwar period,andfurthermoreexpandedthecollaborationsdevelopedintheFirstWar,to provideabetterinfrastructureforthebiologicalandclinicaltestingofnewdrugs.
11
J.LiebenauPatentsandtheChemicalIndustry:ToolsofBusinessStrategyinJ. Liebenau(ed.),(1988):13550.
430
ConcludingComments
431
Thesignificantadvancesmadeinmanufacturingduringtheinterwarperiodwere summarisedbyFrederickGambleandNormanEvers.Theextractionofhormonesbore littleresemblancetotheearlierextractionofalkaloids.Manufactureoftheseproducts requiredadelicacyofcontrolbeyondanywhichhadpreviouslybeenavailable:infactit wouldhavebeenimpossibletomakeinsulinonalargescaleafewyearsbeforeits discovery.Thecontrolofhydrogenionconcentrationswasessentialandhugeamountsof alcoholandothersolventswereneededandmethodshadtobedevelopedtorecoverthese. Evaporatingplantwasrequiredtoresistbreakdownbytheacidsusedandinthisrespect thereplacementofcoppervesselswithstainlesssteelhadbeenvital.Oldmethodsof filteringwerealsoinadequateandhighspeedcentrifugaldeviceshadbeeninstalled. Sterilisationtechnologyalsohadtobedevelopedsothatlargevolumescouldbesterilised withouttheuseofheat,andthiswasdoneusingasbestosbasedSeitzfilters,which allowedrefrigeration.Specialirradiationtechniqueshadtobedevelopedtoprepare
13 vitaminDandnewtechniqueshadbeendevelopedforpreparingemulsions.
Throughtheworkonstandardisationofdrugs,BritishscientistssuchasTrevan, GaddumandBurnmadeimportantstatisticalcontributionstotheunderstandingof biologicalvariation,andBritishfirmstookadvantageofthis,andtheirstronglinkswith physiologistsandtheexpertiseinalkaloids,toproducenewstandardisedalkaloids,and helptoidentifytheactiveconstituents.Althoughtheactualdiscoveriesmightbecredited toanexternalacademicsuchasChassarMoirwithergometrineorDoddsandRobinson withthesynthesisofstilboestrol,theycollaboratedwithindustryandtheirdiscoveries wereonlymadepossiblebytheprovisionoflargemanufacturedquantitiesoforgan extracts.However,whenitwasdiscoveredthatexistingpatentsdidnotcovertheactive ingredientofProntosil,Britishfirmsrapidlyseizeduponthisopportunityandproduced andpatentedtheirownchemicallydistinctsulphonamides.Thisinvolvedthechemical synthesisofhundredsofderivativesandtheirevaluationinthelaboratoryandwith externalconsultants.May&BakerworkedcloselywithLionelWhitby,apathologistat theMiddlesexHospitalandrapidlymasteredthelargescalemanufacturing. Hillsummarisedtheprogressmadeby1935:thewholefoundationofpharmaceutical manufacturehasbeenundergoingachange,atfirstgradualbutinthelateryears increasinglyrapid.
13
ConcludingComments Hecontinued:
432
themanufactureoforganotherapeuticproductshasbecomeahighly organisedsectionofthefinechemicalindustry.Itinvolvesthesynthesisof complexsubstances,andalsotheseparationandpurificationofnatural principlesfromanimalsourceschallengingthesupremacyofsynthetic 14 organicchemicalswhichhaveheldswayforseveralgenerations. Althoughtheproductionofdrugshadincreasedsignificantlytherewerestill concernsattheMRCthatBritainwascopyingratherthandiscoveringdrugsandthatthis stillplacedthecountryatrisk.TheMRCreportof1936hadkickedoffthiscontroversy, hotlydisputedby Britishpharmaceuticalfirmsbywriting:thediscoveryandproduction ofchemicalcompoundsofvalueinchemotherapyhasdependedalmostentirelyon Germanscienceandindustryandstillsodepends,asituationwhichintheeventofwar couldbefraughtwithgravedanger.TheABCMcountered:duringthelast20yearsthe BritishChemicalIndustry,withthestimulusoftheKeyIndustrydutieshasmadesuch greatstridesthatthepositionwasvastlydifferentfromwhatitwasin1914.Mostofthe syntheticproductswhichareessentialtothehealthservicesoftheEmpirearenow manufacturedinthiscountryinadequatequantities.Patentsprotectedafewbutitwas feltthattheycouldbemadeunderlicense.TheMRChadinvested30,000fornew researchin chemotherapybutmostofthecostsweretakenupbyspendingonnew
15 buildingsfortheNIMRatMillHill.
432
ConcludingComments
433
Mr.DavidAdams,LabourM.P.forConsett,askedthePresidentoftheBoardof
th TradeaquestioninParliamenton20 May1938abouthowsuccessfulBritainhadbeenin
replacingGermanimports.Thelatestdata(from1935)showedthatoutputofSalvarsan likecompoundsinBritainwas7,900lbs.(equivalentto107,000).Adamshad specificallyaskedaboutthelevelofimportsofthekeyGermanantiinfectiveproducts Salvarsan,Neosalvarsan,Bayer205,tryparsamide,Atebrin,Plasmoquine,trypanblueand Trypaflavin.Thesewerenotseparatelyrecordedbutin1933therewereimportsofonly69 lbs.ofSalvarsan,neosalvarsanandorganicarsenicals.Britainhadclearlyovercomea relianceonGermanyforthisdrug.Themainproblemwithimportswasnotthe2.5mof theNHIdrugbillbuttheUKspendof2028monpatentmedicinesandthisexplainsthe constantfocusofthegovernmentandBMAonthesesecretremedies.FredGamble confirmedthattheuseofsecretandproprietarymedicineshadincreasedandthatpriorto 1932thiscountrywasthedumpinggroundoftheworldandstillistosomeextentin spiteofthefactthat,withtherarestexceptionsBritishpharmaceuticalfirmscan
18 manufactureallthatisrequired.
ConcludingComments
434
ABCMtookonitsowninitiative,activestepstopromotethemanufactureofthose medicinalchemicalsthenimportedfromGermanyandlikelytobeessentialintheeventof
23 warsotherewouldbenoshortages. 24 By1939allofthemajorBritishfirmsproducedawiderangeofvitaminproducts.
Britishfirmshadnotincreaseddramaticallyinsize,withonlyICIapproachingthesizeof theGermangiants.HoweverfirmssuchasGlaxoandAllen&Hanburyshadbecome
19 20
DrugsinWarTime,PharmaceuticalJournal (22April1918):40304. HerbertLevinstein,ProgressoftheBritishChemicalIndustry,Pharmaceutical Journal (13March1937):264. 21 J.Davidson Pratt,TheEconomicsoftheFineChemicalIndustry,Chemistryand Industry (20January1951):38 22 CeliaPetty,PrimaryResearchandPublicHealth:thePrioritisationofNutrition ResearchinInterwarBritaininJ.AustokerandL.Bryder(1989):83108. 23 ABCMReportontheChemicalIndustry (London:ABCM,1949).
434
435
primarilyaretailbusinessmadeprofitsof776,292,J.Nathan(theforerunnerofGlaxo)
25 made90,647,BDHmade49,790andEvansmade39,140. 26 BritainwaswellpreparedfortheSecondWorldWarintermsofdrugsupplies.
TheABCMhadcontinuedtocatalogueessentialdrugsandtheirmanufacturers. BurroughsWellcomereviewedalistof40suchGermandrugsattheirSTCmeetingon29 September1939.Fivewerealreadybeingproduced,andadozenorsowereconsidered notworthmaking,butplansweremadetomanufacturetheremainder,aslongaschemical intermediatescouldbeobtainedfromICI,andmostwereinhandbyNovember.The mergerofmanydyestuffsandalkalifirmstocreateICIhadresolvedmanyofthe problemsof theprovisionofchemicalintermediatesforpharmaceuticalmanufacturers.It wasrecognisedthattherecentGermandrugssuchasAtebrinandPlasmoquinewould havetobereplacedintheeventofwarandthiswasoneofthereasonsbehindthegranting
27 offundsforresearchinchemotherapy.
ThemainchallengetoBritainintheSecondWorldWarwastopreparesynthetic versionsoftheantimalarialsthatBayerhadrecentlydeveloped,andthiswastobea
28 collaborativechallenge,withICIplayingaleadingroleduringthewar. Burroughs
TheVitamins,PharmaceuticalJournal (21January1939):5459. Figuresarequotedfrom PharmaceuticalJournal 143(1939)asfollows:ICI(25 March1939):322Boots(3June1939):884J.Nathan(14January1939):49BDH(8 April1939):377andEvans(11March1939):269. 26 AssociationofBritishChemicalManufacturersPharmaceuticalSpecialities:British nd EquivalentsandAlternativesforForeignProprietaryProducts(London:ABCM,2 edition1940) 27 ParliamentaryNews.ImportsofFineChemicalPharmaceuticalJournal 140(28 May1938):581ThePatentMedicineTrade.ProfA.J.ClarksIndictment, PharmaceuticalJournal 140(14may1938):518. 28 D.Greenwood,ConflictsofInterest:theGenesisofSyntheticAntimalarialAgents inPeaceandWar.J.AntimicrobialChemotherapy 36(1995):85772A.S.MacNalty, HistoryoftheSecondWorldWarMedicalResearch sectioneditedbyF.H.K.Green, G.Covell,(London:HMSO,1953):9,15559. 435
ConcludingComments
436
62206624 13345 8
7325 101227024
29
ConcludingComments
437
regardtoethicaldrugsupplies.Whilethiswasnottherouteofmajordrugdiscoveriesthat othershavesought,itdoesexplainhowandwhyBritainsurvivedthetwoworldwars.For thosewhodetractfromtheachievementsoftheindustry,noexplanationhasbeenoffered astohowtheindustrydidbecomesuccessfulinBritainasitcertainlyis. Regardingclinicaltrials,thesulphonamidesinparticular,andsynthetichormones, wererecognisedasimportantbydoctors,helpingtoovercometheirreluctancetobe involvedinclinicaltestingsoitwasnolongerdifficulttofinddoctorswillingtotestthese excitingnewtherapies.Andheremyworkcanbecomparedwiththatofotherhistorians oftrials.AlanYoshiokiconcentratedhisresearchonthefirstsignificantrandomised controlledclinicaltrials,ofstreptomycin(anotherexternaldiscoveryfromAmerica)
34 organisedbetween1946and1948bytheMRC. Hisresearchtopicrelatestoanother
33 34
J.DavidsonPratt,(1951):38 AlanYoshioka.Streptomycin,1946:BritishCentralAdministrationofSuppliesof aNewDrugofAmericanOriginwithSpecialReferencetoClinicalTrialsinTuberculosis MedicalResearchCouncilStreptomycininTuberculosisTrialsCommittee,(Universityof London:PhDThesis,1998)AlanYoshiokaStreptomycininPostWarBritain:aCultural HistoryofaMiracleDruginDrugsonTrial,ClioMed.(1999):53Streptomycin TreatmentforPulmonaryTuberculosis:aReportoftheStreptomycininTuberculosis TrialsCommitteeBritishMedicalJournal (30October1948):769782. 437
ConcludingComments
438
35 evolutionarypathoftrialsintheUSAasdescribedbyHarryMarks, althoughBradford
Hill,theMRCstatisticianforthestreptomycinwashighlyinfluentialinspreadingthis
36 methodologytotheUSAthroughaseriesoflectures. Thestreptomycinstudystimulated
DavidCantorexaminedstudiesofcortisone,whichaseriesofcompanies,includingBDH andBootsworkedoninthe1950s.Morerecentlyithasbeenlefttoscientiststorecall
39 theirownearlyeffortsinthetestingofnewdrugs. Quirke,SlinnandTweedalealso
offersomefurtherinsightsintolaterdevelopments. AlthoughQuirkeandCoxMaksimovarguedforaprogressionfromtheTTC modelthroughtotherandomisedcontrolledtrials,Iammoresceptical.Iexaminedallof theTTCstudiesandsawhardlyanyevidenceofstatisticalinput,andtheTTCcommittee weresatisfiedtoevaluatethedrugsinasmallseriesofpatientsandproclaimabenefitor not.Inparallel,theMRCwereperformingquitesophisticatedepidemiologicaland vaccinestudies,involvingstatisticians.AsValierargued,theMRChadlesscontrolover thebedsidethanthelaboratory,butIbelievethattherewasamajordifferencebetween offeringavaccineornotforadiseasethatmightoccur,asopposedtoofferingadrugora placeboforanactivediseasethatneededtreating.TheTTCwasnotformally reconstitutedpostwarbutasignificantnumberofmostlyforeigncompanies,especially
35
HarryM.Marks.IdeasasReforms:TherapeuticExperimentsandMedicalPractice, 19001980(MassachusettsInstituteofTechnology,BostonMass:PhDThesis,1983).
36
ReportofaConferenceonthePlaceofStatisticalMethodsinBiologicaland ChemicalExperimentation(2829January1949)Ann.NewYorkAcad.Sci.52(1950): 789D.Maitland,TheClinicalTrial,SomeDifficultiesandSuggestionsJ.Chronic Diseases11(1960):48496. 37 HarryM.Marks,(PhD.thesis,1983)H.M.Marks,NotesfromtheUnderground. TheSocialOrganisationofTherapeuticResearchinD.Long,R.Maulitz(eds.),Grand Rounds:100yearsofInternalMedicine,(Philadelphia:UniversityofPennsylvania,1987) H.M.Marks, TheProgressofExperiment.ScienceandTherapeuticReforminTheUnited States,1900 1990(Cambridge:CambridgeUniversityPress,1997).
38
ConcludingComments CIBA,establishedfurthertrialswiththeTTCasacoordinatingbody.Themajorityof
439
MyhopeisthatIhavenotonlyansweredmyownquestions,buthavealsoraised somefurtherquestionsworthyofmoredetailedstudy.Iwouldliketohavepursuedthe careerofFrancisCarrtocompletehisbiography,andfurtherstudyofhisworkatBoots andBritishDrugHouseswouldbeof value.Ionlyexploredhiscampaignsforchemical engineeringtrainingtoalimiteddegree,anddidnotdivertintohiscommitteeworkon wargasesandonpatents.EquallytherewasagreatdealofdetailonthecareerofFred PowerthatIhadtoomit,andamoredetailedaccountofthescopeofchemistryperformed atBurroughsWellcome18961914wouldbevaluable.Iamcertainthatamoredetailed studyofthecomplexthemesofensuringdrugsuppliesduringtheWorldWarsis warranted,utilisingsourcesatthePROandtheRoyalSociety. Thisthesishasbeenwiderangingbuttherearesomeclearpointstoemerge: SyntheticchemistrybecameimportantfarearlierinBritainthanwas previouslyrecognisedbutitwasinitiallyusedforcheckingthepurityand standardsofextracts. BurroughsWellcomewasanimportantsourceofmanufacturingchemists forothercompaniesFrancisCarrwasanimportantchemicalengineerand playedacentralroleindevelopingthesyntheticdrugindustryinBritain. Britishfirmscampaignedforclinicaltestingoftheirdrugs thiswasnot somethingimposeduponthem.TheMRCledstudiesoftheTTCwerenot basedonstatisticalprinciplesormodeledonearlierinsulinstudies. AseriesoffactorscontributedtothesuccessoftheBritishindustryintheinterwarperiod. ItwasnotjusttariffprotectionorthenewTherapeuticSubstancesActbutalsothe emergenceofnewtypesoforganotherapyandvitamins,whichhelpedthemtomake profitswhilebuildingtheirmanufacturingcapacity.TheimportanceBritishsuppliesof chemicalintermediatesandsolventsshouldnotbeunderestimated.
439
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