BRITISHPHARMACEUTICALINDUSTRY, SYNTHETICDRUGMANUFACTUREANDTHE
CLINICALTESTINGOFNOVELDRUGS 18951939.
AthesissubmittedtotheUniversityofManchesterfor
thedegreeofDoctorofPhilosophyintheFacultyof LifeSciences,2005.
KeithJohnWilliams CentrefortheHistoryofScience,Technologyand
Medicine.
Listofcontents,abbreviationsanddeclarations
2
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
3
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
4.12
Conclusions.
206
CHAPTERFIVE:PostWarProblems,PatriotismandProtectionism:
IndustryledCampaignsandtheRiseofFrancisCarr. 5.1 5.2 Introduction.
PostWarCampaignsfortheProtectionofthePharmaceutical Industry. 5.3
5.4 5.5 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 5.5.6 5.6
TheABCMMissiontoGermanManufacturingSites.
TheSankeyJudgementanditsConsequences.
BritishPharmaceuticalFirmsPostWar. May&Baker. Boots. Howards.
Glaxo. Allen&Hanburys. BritishDrugHouses.
ProtectingtheBritishPublic:TheMRCandtheNational
InstituteofMedicalResearch(NIMR) Biological
StandardisationandGovernmentLegislationofDrugs. 5.7
ChemicalWorkersinBritain:FrancisCarrandChemical 245 210 213 219 220
221 223 223 225 227 229 207 208
Listofcontents,abbreviationsanddeclarations Engineering. 5.8 5.9
PostWarGermanyandOtherForeignCompetition. Conclusions. 249 254
5
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
6
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
7
CHAPTERNINE Conclusions. BIBLIOGRAPHY
440 484.
Listofcontents,abbreviationsanddeclarations ABBREVIATIONS
A&H ABCM AGFA BASF BDH BIPM BMA BP CIBA DSIR FRS ICRF ICI
IG(Farben) LSHTM M&B MRC Allen&Hanburys
AssociationofBritishChemicalManufacturers
AktiengesellschaftfrAnilinfabrikation,(Berlin)
BadischeAnilinundSodaFabrik BritishDrugHouses
BritishInstituteofPreventativeMedicine(laterListerInstitute)
BritishMedicalAssociation BritishPharmacopoeia
GesellschaftfrChemischeIndustrieBasel
DepartmentofScientificandIndustrialResearch FellowoftheRoyalSociety
ImperialCancerResearchFund ImperialChemicalIndustries
Interessengemeinschaft(orcommunityofinterests)
LondonSchoolofHygieneandTropicalMedicine MayandBaker
MedicalResearchCommittee19131920 MedicalResearchCouncil 1920onwards
NHI NIMR PRO RAMC SCI STC UCH WBSR WCRL WPRL
NationalHealthInsurance NationalInstituteforMedicalResearch
PublicRecordOffice RoyalArmyMedicalCorps.
SocietyoftheChemicalIndustry ScientificandTechnicalCommittee
UniversityCollegeHospital WellcomeBureauforScientificResearch
WellcomeChemicalResearchLaboratory
WellcomePhysiologicalResearchLaboratory
8
Listofcontents,abbreviationsanddeclarations
9
ABSTRACT
BritishPharmaceuticalIndustry,SyntheticDrugManufactureandthe
ClinicalTestingofNovelDrugs18951939.ThisthesisaddresseshowandwhenBritishpharmaceuticalfirmsfirst
manufacturedsyntheticdrugs,andhowtheypersuadeddoctorstotestnoveltherapiesin
clinicaltrials.EdwardianBritainwasreliantonGermanyforsyntheticdrugs,sohowdid
BritishfirmsmeetthischallengeintheFirstWorldWar,andhowwasthisnewformof
theBritishpharmaceuticalindustrynurturedintheinterwarperiod?
Previousstudieshavecoveredtheindustrysoriginsinpharmacyrootsand
dyestuffs,andthegrowthoftheAmericanindustry,butwithoutanoverallsynthesis.
ThereareseveralgoodcompanyhistoriesforBritain,andRobsonandQuirkecompared
pharmaceuticalsinFranceandBritain,whilstTanseyexaminedphysiologicalresearchat
BurroughsWellcomebutlittlehasappearedonchemicalresearchandsynthetic
manufacture.IwillemphasisetheworkofFrancisCarrwhodevelopedsyntheticdrugsat
BurroughsWellcome,BootsandBritishDrugHouses.Asfortesting,theliteraturecovers
earlystatisticsandtheclinicaltrialsofmajorbiologicaldrugssuchasinsulinbutthese
didnotoriginatewithindustry.Withsyntheticandothernoveldrugs,asIshow,firms
founditdifficulttoarrangeclinicaltrialsandtheyturnedtotheMRCforassistance.I
examinethesenegotiationsandtrialsinsomedetail.
Chapter1reviewsthehistoriographyofthepharmaceuticalindustryandthe
clinicaltestingofdrugs.Chapter2examinesthevariedoriginsoftheindustry,contrasting
ethicalandpatentmedicines,andcomparingBritainwithGermanyandAmerica.Chapter
3showshowBurroughsWellcomecombinednoveldrugsinsophisticateddosageforms,
adoptingnewsalesstrategiesandestablishinglaboratoriestostandardisedrugs.Their
experienceinsmallscalesynthesisfrom1896enabledthemtoprepareGermandrugs
whenpatentswereabrogatedintheFirstWorldWar(chapter4).TheMRCandother
firmspoachedBurroughsWellcomeresearchers,andtheMRCtookstandardisationasa
centraltheme,soestablishinganinternationalreputation.Chapter5addressesthepost
warcampaignsfortariffprotection,andtheextensionofMRCdrugevaluationsasBritish
firmsstrovetoremaincompetitive.Novelvitaminandhormonaldrugsallowedthemto
expandtheirmanufacturingcapacitywhilegainingfurtherexperienceofdrugsynthesis.
Chapter6describeshowBritishfirmscampaignedforclinicaltestingofdrugsfrom1922
1930andexplainswhyaTherapeuticTrialsCommittee(TTC)wasestablishedin1931.
Chapter7examinesthestrategyofBurroughsWellcomepostwar,byanalysingthe
strategicdebateswithintheirScientificandTechnicalCommittee.Chapter8examinesthe
TTC,howtheyfavouredBritishdrugs,andhowstudiescomplementedtheirownresearch
interestsitprovidesinsightintotheresearchstrategiesofBritish(andforeign)firms,plus
anassessmentoftheTTCasseenbytheMRCandbycompanies.Chapter9offersgeneral
conclusionsandcontraststhepositionofBritishmanufacturersattheoutbreakofthe
SecondWorldWarwiththeirpositionattheoutbreakoftheGreatWarinAugust1914.
Someopportunitiesforfurtherworkarethenidentified.
Listofcontents,abbreviationsanddeclarations
10
DECLARATIONNoportionoftheworkreferredtointhisthesishasbeensubmittedinsupportofan
applicationforanotherdegreeorqualificationofthisoranyotherUniversityorother
Instituteoflearning.
COPYRIGHTDECLARATIONCopyrightinthetextofthethesis/dissertationrestswiththeauthor.Copies(byany
process)eitherinfull,orofextracts,maybemadeonlyinaccordancewithinstructions
givenbytheAuthorandlodgedintheJohnRylandsUniversityLibraryofManchester.
DetailsmaybeobtainedfromtheLibrarian.Thispagemustformpartofanysuchcopies
made.Furthercopies(byany process)ofcopiesmadeinaccordancewithsuch
instructionsmaynotbemadewithoutthepermission(inwriting)oftheAuthor.
Theownershipofanyintellectualpropertyrightswhichmaybedescribedinthis
thesis/dissertationisvestedintheUniversityofManchester,subjecttoanyprior
agreementtothecontrary,andmaynotbemadeavailableforusebythirdpartieswithout
thepermissionoftheUniversity,whichwillprescribethetermsandconditionsofany
sucharrangement.
Furtherinformationontheconditionsunderwhichdisclosuresandexploitationmaytake
placeisavailablefromtheHeadoftheCentrefortheHistoryofScience,Technologyand
Medicine.
Listofcontents,abbreviationsanddeclarations
11
ACKNOWLEDGMENTSOvertheseveralyearsithastakentowritethisthesisIhavemanyindividualstothank.
FirstlyIwouldliketothankmyoriginalandfinalsupervisorJohnPickstoneatthe
ManchesterWellcomeUnitfortheHistoryofMedicinewhohassolidlysupportedme.
Severalotherslookedaftermeatvarioustimes.InparticularIwishtoextendthanksto
SteveSturdy,whomovedtoEdinburghpartwaythroughandbeforehimGeoffrey
Tweedalewhogavemeinitialguidance.AtvariouscongressesandmeetingsIhave
receivedencouragementfromJudySlinn,andDesireCoxMaximov.
Morerecently
VivianneQuirkecommentedonsomeofmyearlydraftchapters.Ioweagreatdealto
JohnDavies,whowasthearchivistattheWellcomeInstitute,inLondonandtoMrs.
MaryNicholas,attheMRC.Archives,beforetheirmovetothePRO.
ThanksalsotoJulieSheppard,archivistandherassistantLesleyHallatthe
ContemporaryarchivecentreandarchivistsattheRoyalSocietyandtheImperialInstitute
andJ.M.LevertonintheresearchlibraryatBootsPharmaceuticalsandtoMrs.Barbara
RobertswhokindlyforwardedtwobooksatonetimeownedbyThomasHenryof
BurroughsWellcome.
IalsoreceivedsupportfromthelibrariansattheRoyalSocietyandatAstraZeneca,
thoughwhenIstarteditwasImperialChemicalIndustriesLtd.ThanksalsotoMichael
PayneandJanetteMackinatTheBritishLibrary,BostonSpa,Wetherbyforhelpingto
trackdownsomerelatedtheses.Finallyspecialthankstomyparentswhohavesupported
methroughthisprolongedexperienceandtoLorraine,Jane,ClaireandNeilespecially.
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
12
CHAPTERONE:GeneralIntroduction,AimsandScopeofthisThesis.1.1BackgroundtotheThesis.
Thecentralquestionsofthisthesisare:
HowdidBritishpharmaceuticalcompaniesfirstpreparenovelsyntheticdrugs,andhow
didtheygetdoctorstotesttheseandtheirothernoveldrugsinclinicaltrials?
Thequestionarosebecausethemodernpharmaceuticalindustryisbasedlargelyon
novelsyntheticdrugs.DuringtheFirstWorldWartheimportanceofaBritish
pharmaceuticalindustrybecamerecognisedandBritishfirmsswitchedfrompreparing
drugsattherequestofphysicians,toofferingcompletelynovelagentsthatweretobe
testedforthefirsttimeinman.ManyofthesehadpreviouslycomefromGermany.Notall
weresynthetic,buttheywereuniqueintheirpotency.Thewiderquestionsthatemerged
concernhowBritaincompetedwithGermanyintheinterwarperiod,andhowBritishfirms
definedtheirstrategiesofdrugdevelopment,todecidewhethertocommittoproducing
syntheticdrugsasopposedtoplantandanimalextracts,inorganicdrugsandantisera,and
whatinternalandexternalfactorswereconsideredinmakingthesedecisions?Wasit
necessaryforBritishfirmstofollowaGermanmodelorindeedanAmericanmodelofdrug
research?
Thethesisisthereforebroaderinscopethanoriginallyplannedanddemonstrates
howcloseinterrelationshipswereforgedinBritainbetweenindustry,academia,
governmentandmedicalresearch,particularlyfortheperiod19141939.Itevaluates
significantstructuralchangeswithintheframeworkoftheBritishPharmaceuticalindustry,
fromsmallfamilyownedfirmsoperatingindependently,tolargerbusinessesthat
recognisedtheirinterdependenceandthevaluesofcollaborationandnegotiationthrough
a representativetradebody.
WhentheFirstWorldWarwasdeclared,BritainwasdependentonGermanyfor1
syntheticdrugs,aswellasmanyalkaloidsandchemicalintermediates.
HowdidBritish
pharmaceuticalfirmssynthesisecomplexessentialdrugswithinweeksoftheoutbreakof
1
W.Ormandy,BritainandGermanyinRelationtotheChemicalTradeinW.M.
Gardner,TheBritishCoalTarIndustry,ItsOrigin,DevelopmentandDecline(London:
Williams&Norgate,1915):335350.
12
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.
13
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
14
InthelatterchaptersIexamineaseriesoffactorsthatinfluencedhowBritishfirms
gottheirnewdrugstested.Firstlythey
collaboratedwiththeMRCandthePharmaceutical
Societytodemonstratethatbiologicalcompoundswerestandardised,andthenthey
negotiatedameansofclinicaltesting.Akeypointaboutthesechaptersisthattheyconsider
thedrugsthatBritishindustrywasproducingandnotsuccessfulimporteddrugssuchas
insulin.TheMRCbuiltupanetworkofresearchcentresthatbecametheircentresfor
clinicaltrials,buttheycontrolledaccesstothephysicians,somuchsothatwhenBritish
firmsdiddevelopimportantnovelcompounds,theybegantoemploytheirownphysicians
inthe1930stomanagetheprocessofestablishingclinicaltrials.Acombinationoffactors
thereforeledtothesuccessoftheBritishfirmsprotectionfromGermany,synthetic
chemistswithmanufacturingexpertise,theestablishmentoflaboratories,theintroduction
ofnovelorganotherapiesandvitaminsandphysiologysupport,andtheassociatedincreased
manufacturingcapacity.Importantly,collaborationswerealsoestablishedwithuniversity
chemistsandwiththeMRC,whichthenallowedtherapiddevelopmentofnovelvariantsof
sulphonamidesfrom1936.TheBritishpharmaceuticalindustrywasakeypartnerindriving
thisforward. 1.2GeneralIntroductionandHistoriography.
AlthoughthereareseveralgeneralaccountsofAmericanandBritishpharmaceutical
firms,therehasnotyetbeenageneralsynthesisofhowthemodernBritishpharmaceutical2
industrydeveloped,andoftheexternalfactorsinvolved.
Therehavebeenaccountsof
individualcompanieswithlongpedigreesinpharmacy,butnonefocusingonchemistryand3
largescaledrugsynthesis.
Thehistoriographyofdrugshasfocusedalmostexclusivelyon
2
J.T.Mahoney,TheMerchantsofLife:anAccountoftheAmericanPharmaceutical
Industry
(NewYork:Harper,1959)S.Miall,HistoryoftheBritishChemicalIndustry
(London:ErnestBenn,1931)F.N.L.Poynter,TheEvolutionofPharmacy
(London:
Pitman,1965)C.J.Thomas,ThePharmaceuticalIndustryinDuncanBurn(ed.),The
StructureofBritishIndustry
volume2(Cambridge:CambridgeUniversityPress,1958): 33175.3
E.M.Tansey,Pills,ProfitsandPropriety:theEarlyPharmaceuticalIndustryin
BritainMedicalHistory
25.3(1994):15157JonathanLiebenau,TheRiseoftheBritish
PharmaceuticalIndustryBritishMedicalJournal (3October1990):72428
Goldonthe
Green:50YearsofGlaxoatGreenford(London:Glaxo,1985)D.ChapmanHustonand
E.C.Cripps,ThroughaCityArchway,theStoryofAllen&Hanburys17151954
(London:JohnMurray,1954)S.Chapman,JesseBootofBootstheChemist
(London:
Hodder&Stoughton,1974)BootsPureDrugCo.Ltd.(Nottingham:Boots,1938)R.P.
14
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
15
majornaturaldrugssuchasinsulinandpenicillin,ratherthandrugsinventedbythe
pharmaceuticalindustry.ThesehistoriesthereforegivenoinsightintohowBritish4
companiesdevelopedproductsoftheirownresearch,orthestrategiestheyfollowed.
Thisintroductionoutlinesthepreviousworkdoneinthisfieldandidentifiessomeof
thegaps.Chapter2developsthedetailsofhowthepharmaceuticalindustryevolved,sothe
frameworkisdescribedonlybrieflyhere.Acommonthemeisthathistorianshavetriedto
categorisetheBritishindustryassuccessfulornotbymeasuringhowitcomparedwith
Germanyintermsofsyntheticdrugs,orwithAmericaintermsofexternalcollaborations,
oftensimplifyingacomplexissuebythechoiceofunrepresentativecasestudies.Economic
historianshavedescribedhowthegeneralgrowthof
thepharmaceuticalindustrywas5
achievedbydiscoveringnewdrugs,withoutgivinganinsightintohowthiswasachieved.
Insomecases,theymeasuredsuccessbysimplycountingthenumberofpatentsfiledor
salesfigures,whichmaybeverymisleading,especiallyifthefirmhadinterestsotherthan
justpharmaceuticals,asmanydid,oriftherewereaseriesofsimilarproducts,someof6
whichnevermadeittomarket.
Companypoliciesonpatentingcertainlyvariedgreatly.
T.DavenportHines,J.Slinn,Glaxo,AHistoryto1962
(Cambridge:Cambridge
UniversityPress,1992)GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen
&HanburysandtheBritishPharmaceuticalIndustry
(London:JohnMurray,1990)Judy
Slinn,AHistoryofMay&Baker18341984(Cambridge:Hobsons,1984).4
GladysHobby,Penicillin:MeetingtheChallenge(NewHaven:YaleUniversityPress,
1985)H.F.Dowling,FightingInfection:ConquestsoftheTwentiethCentury
(Cambridge,
Mass:HarvardUniversityPress,1977)R.Hare,TheBirthofPenicillin,andtheDisarming
ofMicrobes
(London:GeorgeAllen&Unwin,1978)R.Hare,NewLightontheHistory
ofPenicillinMedicalHistory 26(1982)1.5
W.DuncanReekie,M.H.Weber,Profits,PoliticsandDrugs(London:MacMillan,
1975)MichaelH.Cooper,PricesandProfitsinthePharmaceuticalIndustry
(Oxford:
PergamonPress,1966)W.DuncanReekie,TheEconomicsofthePharmaceuticalIndustry
(London:MacMillanPress,1975)BjornLundgren(ed.),PharmaceuticalEconomics
(Stockholm:TheSwedishInstituteofHealthEconomics,1984)D.Schwartzman,
InnovationinthePharmaceuticalIndustry
(Baltimore:JohnsHopkins,1977)Sainsbury
Report:CommitteeofEnquiryintotheRelationshipofthePharmaceuticalIndustrywith
theN.H.S.19657(London:HMSO,Cmnd.3410,1967).6
J.Kemp,PharmaceuticalPatents:InBritain,India,Italy,JapanandtheUSinG.
TeelingSmith(ed.),InnovationandtheBalanceofPayments:theExperienceinthe
PharmaceuticalIndustry
(London:OfficeofHealthEconomics,1967):23J.Liebenau,
15
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
16
Thepoliticsandmarketingofdrugshavedominatedmorerecentinvestigations.The7
OfficeofHealthEconomics
hassupportedtheindustry,whilemanyauthorshavebeen 8 9
criticalofdrugsafety, pricing
,promotion,animaltesting,ormorerecently,policiesin 10
developingandmarketingdrugsfortheThirdWorld,
oftenfrompreconceived
11 positions.
Haber,inhisotherwiseexhaustivediscussionofthechemicalindustriesin1971
concluded:Thereisnotenoughmaterialonthegrowthofproprietarymedicinesand,
duringtheearlypartofthepresent(twentieth)century,ofthepharmaceuticalindustry.He
wenton:Althoughitwouldencountergreatobstacles,astudyoftheearlyyearsofthe
pharmaceuticalindustryintheprincipalcountrieswouldmakearewardingcontributionto12
moderneconomichistory. InhisearliervolumeHaberhadstated:
Economichistorianshavefrequentlydescribedthedevelopmentof
technologyinindustriesinwhichchangewassimpleandhaveneglectedthe
PatentsandtheChemicalIndustry:ToolsofBusinessStrategyinJ.Liebenau(ed.),The
ChallengeofNewTechnology:InnovationinBritishBusiness(Aldershot:Gower,1988).7
G.TeelingSmith,ThePharmaceuticalIndustryandSociety:AStudyoftheChanging
EnvironmentandEconomicsoftheInternationalIndustry
(London:OfficeofHealth Economics,1972).8 9
A.Chetley,ProblemDrugs(London:AtlanticHighlands,N.J.ZedBooks,1995).
L.Marsa,PrescriptionforProfits:HowthePharmaceuticalIndustryBankrolledthe
UnholyMarriagebetweenScienceandBusiness(NewYork:Scribner,1997).10
G.Gereffi,ThePharmaceuticalIndustryandDependencyintheThirdWorld
(Princeton:PrincetonUniversityPress,1983)T.Heller,PoorHealth,RichProfits:
MultinationalDrugCompaniesandtheThirdWorld(Nottingham:SpokesmanBooks,
1977)M.Silverman,M.Lydecker,P.R.Lee,BadMedicine:thePrescriptionDrug
IndustryintheThirdWorld(Stanford:StanfordUniversityPress,1992).11
RichardHarris,TheRealVoice(NewYork:MacMillan,1964)C.Medawar,
FailingsofthePharmaceuticalIndustryPharmaceuticalMedicine2(1987):259263
MiltonSilverman,PhilipR.Lee,Pills,ProfitsandPolitics(Berkeley:Universityof
CaliforniaPress,1974)JamesS.Turner,TheChemicalFeast(NewYork:Grossman,
1970)BrianS.Inglis,Drugs,DoctorsandDisease(London:AndreDeutsch,1965)M.
Silverman,TheDruggingoftheAmericas(Berkeley:UniversityofCaliforniaPress,1976)
WyndhamDavies,ThePharmaceuticalIndustry:aMedical,EconomicandPoliticalSurvey
oftheWorldwidePharmaceuticalIndustry
(Oxford:PergamonPress,1967).12
L.F.Haber,TheChemicalIndustry19001930:InternationalGrowthand
TechnologicalChange(Oxford:ClarendonPress,1971):7.
16
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
17
morecomplexbutequallyimportantdevelopmentofchemical 13
manufacture.
Thisquotecapturessomeofthereasonswhythepharmaceuticalindustryhasreceivedlittle
attention,asthefactorsinvolvedarecomplexandmultifactorial,thesourcesarescattered,
andgainingaccesstopharmaceuticalcompanyrecordsisproblematic,eveniftheyexist.
Althoughsomeprogresshasbeenmadeinunderstandingthedevelopmentofthe
pharmaceuticalindustry,Quirkewrotein2000that:historiesofthemajornational
pharmaceuticalindustriesarerelativelyrare,especiallyincomparisonwiththechemical
industry.Itisasectorthatisdifficulttoapprehend(sic)asawholebecauseofits14
complexityduepartlytoitsvarietyoforigins.
Forthepurposeofthisintroduction,Ireferprimarilytothedozenmainauthorsthat
haveprovidedmostofthebackground:manyothercontributionswillbereferredtointhe
mainbodyofthetext.TheseareSwann,ParascandolaandLiebenaufortheAmerican
industry,andLiebenau,RobsonandQuirkeforBritain,(andthelattertwoforFrance).For
clinicaltrials,althoughLiebenausetoutsomeofthegroundwork,recentthesesbyDesire
CoxMaksimovandHelenValierhavedevelopedthistheme,withsomereferencetoHarry
MarksforAmerica,whileforcompanyhistoriesthemostexhaustivemodernhistoric
accountshavebeenbyTweedale,DavenportHinesandSlinnregardingAllen&Hanburys,
GlaxoandMay&Baker.ForBurroughsWellcometherehavebeennumerous
contributions,themostimportantformebeingthatofTansey,whoexplainedthe
backgroundtothedevelopmentofthePhysiologicalLaboratoriesandthelicensingofthe
laboratory,allowingmetofocusprimarilyonthechemicaldevelopmentswithinthe15
laboratoriesinwhichnewdrugswerecreatedtoreplacenaturalextracts.
Otherhistories 16 havefocusedonHenryWellcomehimself.
13 14
L.F.Haber,(1958):ix.
VivianeQuirke,ExperimentsinCollaboration:TheChangingRelationshipBetween
ScientistsandPharmaceuticalCompaniesinBritainandinFrance,19351965(University
ofLondon:PhDthesis,1999).15
E.M.Tansey,TheWellcomePhysiologicalResearchLaboratories18941904:the
HomeOffice,PharmaceuticalFirmsandResearchExperimentsMedicalHistory
33 (1989):141.16
HelenTurner,HenryWellcome,theMan,hisCollectionandhisLegacy
(London: Heinemann,1980).
17
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
18
Nineteenthcenturypharmaceuticalmanufacturingexistedintwomainformsinallof
themajorcountries.Ethicaldrugfirmsmanufacturedsciencebaseddrugsforphysicians,
withemphasisonactiveprinciples,anddifferentiatedtheirproductsfromotherfirmsbased
onthenoveltyoftheirtabletsorpills,theirstrength,thelevelofimpurities,theirbenefits
andtolerance,andlaterpharmacologicalexperimentsandclinicalexperience.
Patent
medicineswereadvertiseddirectlytopatients,withfancifulnamesandextravagantclaims.
Formanyyearsthetwosystemscoexistedbutthemedicalprofessionbecameincreasingly
criticaloftheunsubstantiatedclaimsofpatentmedicines.TheBritishMedical
AssociationsSecretremedycampaignsin190709highlightedtheunreliabilityofpatent
medicines,andconcernsaboutadulteratedmedicinesinAmericaledtolegislativecontrols17
onsecretremediesandonadvertisingofdrugs.
LegislationinBritaincurbedonlythe
worstexcessesassociatedwithextravagantclaimstheheavyuseofalcohol,narcoticsor
tonicsor,attheotherextreme,thefailuretoincorporateanyknownbeneficial
substances. Anewformoflargescalepharmaceutical
manufactureevolvedinGermanyinthe
lasttwodecadesofthenineteenthcentury,basedonchemicalsynthesisfrombyproducts
ofthedyestuffsindustry.Syntheticdrugsweredevelopedwithassistancefromexternal
pharmacologists.Afurtherdevelopmentaround1891wasdiphtheriaantitoxinandGerman
firmswerewellplacedtotakeadvantageofthisthroughtheirclosecollaborationwiththe
universities.BytheendofthecenturymostGermanfirmshaddevelopedlaboratoriesfor
assayingrawmaterials,forcheckingthepurityofsynthesisedproducts,butalsofor
productresearch,andtestingtherelationshipofchemicalstructuretophysiological
function.
MuchoftheresearchonGermanfirmsfocusesontheevolutionofchemical18
manufacturefromdyesandstatesupport.
IntheEnglishliterature,anexcellentinsight
intothecollaborationofindustrywithPaulEhrlichandotheracademicscientistsisgivenin
17
J.B.Blake(ed.),SafeguardingthePublic:HistoricalAspectsofMedicinalDrug
Control
(Baltimore:JohnsHopkinsUniversityPress,1970):112122,144157.18
T.Lenoir,RevolutionfromAbove:TheRoleoftheStateinCreatingtheGerman
ResearchSystem,18101910TheAmericanEconomicReview(May1998):2227.
18
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
19
19 Bumlersaccount,towhichIreferextensivelyinChapter2.
Beergivesanexcellent 20 accountof
thedevelopmentoflaboratoriesinGermanfirms, whileFox,Haberand 21
Readerprovidebackgroundondyestuffsdevelopments.
ForAmerica,historianshaveconcentratedontheethicalmanufacturersthat
characterisedtheirproductsscientifically,andontherelationshipbetweenindustryand
academia.Liebenaucoveredtheperiodupto1914,showingthatAmericanfirmsflourished
duringandaftertheAmericanCivilWarandwerenotedfortheirdevelopmentofnovel
dosageforms,particularlytablets.HeshowedthatAmericanfirmsadoptedtheGerman
laboratorymodellater,andalsoprepareddiphtheriaantitoxinin1895.Heshowedthat
ParkeDavisemployedachemisttomeasureandstandardiseactiveprincipleswithinergot,
andbothLillyandSearleemployedlaboratorystaffinthe1880s.SmithKline&French
hadananalyticallaboratoryfrom1893andperformedassaysasearlyas1884.However,
Liebenauassumesthattheselaboratoryworkerseventuallygotinvolvedin(unspecified)22
productdevelopment.
Howscientifictheselaboratorieswereisopentodebateas
SwannreportedthatEdwardKendallleftthelaboratoryatParkeDavisin1910becauseof23
thelackofascholarlyatmosphereandbecausehewastreatedlikeafactoryworker.
Swannarguedthatthefoundationsfortheriseofindustrialpharmaceuticalresearchinthe
interwarperiodwereprogressinnaturalsciences,aninstitutionalframework,which
19 20
E.Bumler,PaulEhrlich,ScientistforLife
(NewYork:Holmes&Meier,1984).
J.J.Beer,TheOriginsoftheGermanChemicalIndustry
(Urbana:Universityof
IllinoisPress,1959)J.J.Beer,CoalTarDyeManufactureandtheOriginsoftheModern
IndustrialResearchLaboratoryIsis49(1958)123131.21
M.R.Fox,DyemakersofGreatBritain18561976:aHistoryofChemists,
Companies,ProductsandChanges(Manchester:I.C.I.plc,1987)W.J.Reader,Imperial
ChemicalIndustriesLtd.AHistory:TheForerunners18701926volume1(London:
OxfordUniversityPress,1970)L.F.Haber,(1958)and(1971).22
JonathanLiebenau,MedicalScienceandMedicalIndustry:TheFormationofthe
AmericanPharmaceuticalIndustry
(Basingstoke:MacMillan,1987):5,125Jonathan
Liebenau,"MarketingHighTechnology:EducatingPhysicianstouseInnovative
MedicinesinR.P.T.DavenportHines(ed.),History,BagmenandMarkets:Studiesin
theHistoryofMarketingandBritishIndustry
(Aldershot:Gower,1986):82101,183236.23
JohnP.Swann,AcademicScientistsandthePharmaceuticalIndustry:Cooperative
ResearchinTwentiethCenturyAmerica(Baltimore:JohnHopkinsPress,1988):34.
19
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
20
facilitateditsapplication,andthewillingnessofindustrialiststorecognisetheimportanceof
scienceandofscientiststoworkwithindustrialfirms.24 25 LikeLiebenau
,Swann concludedthatinBritainupto1920,researchdeveloped
fromassaysandlaboratorycontrols,assumingagainthatthoseperformingassaysin
laboratorieslaterbeganperformingresearchfornewproducts.NeitherSwannnor
Liebenaugaveanyevidenceforthis.Oneimmediateconclusionisthatamorecarefully
wordeddefinitionisrequiredofwhatconstitutesresearchandtheremustbeaclear
recognitionthatlaboratoriescomeindifferentforms.Alaboratoryworker,skilledin
performingassaysdoesnotnecessarilyhavetheskillstosynthesiseanddevelopnewdrugs.
Nordosmallstudiesinlaboratoriesequatetodevelopingasuccessfulmanufacturing
procedureandtransferringthistechnologytothemanufacturingworks.26
ParascandolaexaminedpharmaceuticaldevelopmentsinAmerica,
withparticular 27
emphasisonpharmacologyandtheevolvingroleofstructureactivitystudies
andshowed
theimportanceofcollaborationswithexternalpharmacologistsandpharmacistsin
WisconsinandPhiladelphia.28
24
JonathanLiebenau,ScientificAmbitions:thePharmaceuticalIndustry,19001920
PharmacyinHistory 27.1(1985):311J.Liebenau,TheRiseoftheBritish
PharmaceuticalIndustryBritishMedicalJournal
(3October1990):72428.25
JohnP.Swann,AcademicScientistsandthePharmaceuticalIndustry:Cooperative
ResearchinTwentiethCenturyAmerica(Baltimore:JohnHopkinsPress,1988):34.26
J.Parascandola,ThePharmaceuticalSciencesinAmerica,18521902J.Am.Pharm.
Assoc.40.6(2000):73335J.Parascandola,DrugTherapyinColonialandRevolutionary
AmericaAm.J.Hosp.Pharm.5.12(1976):6977.27
J.Parascandola,IndustrialResearchComesofAge:theAmericanPharmaceutical
Industry19201940PharmacyinHistory
27.1(1985):1221J.Parascandola,Structure
ActivityRelationshipstheEarlyMiragePharm.Hist.13(1971):310:J.Parascandola,
TheControversyoverStructureActivityRelationshipsintheEarlyTwentiethCentury
Pharm.Hist.16(1974):5463.28
J.Parascandola,TheFoundingoftheUniversityofWisconsinSchoolofPharmacy
Pharm.Hist.38.2(1996):5161J.Parascandola,J.Swann,DevelopingPharmacologyin
AmericanSchoolsofPharmacyPharm.Hist.25.3(1983):95115J.Parascandola,John
J.AbelandtheEarlyDevelopmentofPharmacologyattheJohnsHopkinsUniversityBull.
Hist.Med.56.4(1982):51227.
20
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
21
29 ForEngland,Tansey
gavethebackgroundtothedevelopmentoflaboratoriesat
BurroughsWellcomeandtheproblemsofovercomingtheantivivisectionistmovementin
Britain.EvenaftertheformationoflaboratoriesinBritain,andespeciallyafterthe
DangerousDrugsActof1923,whenpharmacistshadtobeincharge,QuirkesawBritish
andFrenchlaboratories,asdemandpulledratherthanresearchpushed,andthis30
conclusioniseasytounderstand.However,asTweedalepointedout
,firmssuchasAllen
&HanburysdidnotseethemselvescompetingdirectlywithGermanfirms,evenafterthey31
developedlaboratoriesandthisisapointthatIwilldevelop.Quirke
emphasisedthe
importanceofmajormergerstoformImperialChemicalIndustries(ICI)andRhne
Poulencin1926and1938respectively,thoughIfoundithardtofollowherargumentthat
ICIdevelopedpharmaceuticalsin1926andthesefirmsbecametrendsetters.InfactICI
onlydedicatedastaffofseventoexploratorymedicinalchemistryfrom1936afterthe
discoveryofsulphonamides,andalthoughtheyexpandedtheireffortsduringandafterthe32
SecondWorldWar,theydidnotformapharmaceuticaldivisionuntil1954.
SwannrecognisedthatsomeAmericanfirmsbecameimportantpoolsofscientists,
collaboratingwithpharmacologistsinuniversitiesandmedicalschoolsintheinterwar33
period.
TheexamplesgivenincludedEliLilly,Merck,ParkeDavis,AbbottandE.R.
Squibb,allofwhichevolvedtobemajorU.S.pharmaceuticalmanufacturers.Swann
identifiedthreemaintypesofexternalcollaborator:thegeneralist,thespecialistandthe
projectspecificconsultant,andtheywereprimarilypharmacologistsandchemists.Froma
29
E.M.Tansey,TheWellcomePhysiologicalResearchLaboratories18941904:the
HomeOffice,PharmaceuticalFirmsandResearchExperimentsMedicalHistory
33 (1989):141.30
GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen&Hanburysand
theBritishPharmaceuticalIndustry (London:JohnMurray,1990).31
VivianeQuirke,ExperimentsinCollaboration:TheChangingRelationshipBetween
ScientistsandPharmaceuticalCompaniesinBritainandinFrance,19351965(University
ofLondon:PhDthesis,1999).32
FrankL.Rose,OriginandRiseoftheSyntheticDrugsinF.N.L.Poynter(ed.),
ChemistryintheServiceofMedicine(London:Pitman,1963):179197.IntheRose
accountitsays1954andthemainsiteatAlderleyParkdidnotopenuntil1957.33
JohnP.Swann,(1988):34,3334,45,51,6583Richardsperformedresearchwith
HenryDaleattheNationalInstituteofMedicalResearchinLondon:C.F.Schmidt,A.N.
RichardsBiographicalMemoirsofFellowsoftheRoyalSociety
13(1967):32742.
21
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
22
companyperspectivethebestknownarethecollaborationsofEliLillywithToronto
UniversityregardinginsulinandthecollaborationofHarvardUniversitywithseveralfirms
withlivertherapyforperniciousanaemia.Swannaddressedsomeofthedifficultiesof
collaborativeworkincludingproprietaryinterests,sharinginformationwithoutsiders,
publicationsandpatenting,butconcludedthatthiswasaparticularsuccessforthe
Americanindustry.
VivianeQuirkedrewparallelsbetweenthesystemsthatevolvedinFranceand
Englandupto1965.ShesuggestedthatHenryDaleattheNationalInstituteofMedical
ResearchandErnstFourneauatthePasteurInstituteexhibitedmanyparallelsbothcoming
fromacademicbackgrounds,workinginthepharmaceuticalindustry,thenreturningto
academia,butinvestingheavilyincollaborativeresearch.Shearguedthatcollaborative
workdevelopedwidelyinFranceintheinterwarperioddespitealackofsupport,whereas34
itdevelopedinBritainasaresultofgovernmentsupportandlargelythroughDale.
RobsondescribedtheBritishdrugindustryascomprisingfourdistincttypesoffirm35
attheendofthenineteenthcentury :
1.
Traditionaltradersthatimportedrawmaterials,purifiedandprocessed
them suchfirmsincludedMorsons,Whiffens,May&Baker,Allen&
HanburysandHowards.
2.
Marketingfirmsconcentratingontheretailtrade,exemplifiedbyBoots,
TaylorsandtheLondonDrugCompany.
3.
EdinburghbasedalkaloidmanufacturerssuchasMacFarlans,T.H.Smith
andDuncanFlockhardt.
4.
MoreresearchorientedfirmsincludingBurroughsWellcomeandEvans
Sons,Lescher&Webb.
Thetraditionalfirmshavereceivedlittleattention,exceptinindividualcompany
historiesbyTweedaleandChapmanHuston(Allen&Hanburys),Slinn(May&Baker)34
35
VivianeQuirke,(UniversityofLondon:PhDthesis,1999).
M.Robson,TheBritishPharmaceuticalIndustryandtheFirstWorldWarinJ.
Liebenau(ed.),TheChallengeofNewTechnology:InnovationinBritishBusinessSince
1850 (Aldershot:Gower,1988):82105.
22
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
23
andDavenportHinesandSlinn(Glaxo)andalthoughadefinitivehistoryofBurroughs
Wellcomeisawaited,mostattentionhasfocussedonphysiologicalstandardisationby36
TanseyasBurroughsWellcomeproducedvaccinesandantitoxinsfrom
1895.
RegardingBritishfirmsintheperiodto1940,Liebenauconcludedthat:successful
astheywereinmaintainingtheirsmallbusinessesandaturnoverofbasicproducts,and
givenfewincentivestogrow,BritishfirmssuchasHowards,Evans,Morsons,Bells,
evenAllen&Hanburys,didrelativelylittletoextendtheirmarkets.Hedidnotrefer,asI
do,tothosefirmsthatdidgrowmostsignificantly,namelyBurroughsWellcome,May&37
Baker,BootsandBritishDrugHouses. Inhisthesis,Michael
Robsoncomparedthe
economicsoftheBritishpharmaceuticalindustrywithFranceandSwitzerlandbutagain38
withlittleemphasisonthedevelopmentandtestingofdrugs.
Heexpandedpreviouswork
tocomparethenumberofpatentsandpublicationsfromindustry.However,hisindepth
analysisshowsthatfirmsmayhavedifferedgreatlyintheirpolicy,evenfromproductto
product.
Thesurprisingfindingthereforeisthatthereisasignificantpartofthehistoryofthe
Britishpharmaceuticalindustrythathasnotbeenexamined.Havingreferredtotherhetoric
ofbackwardnessanddeclineininterwarBritainandFrance,Quirkenotesthestronger
BritishpharmaceuticalindustrythatemergedfromtheSecondWorldWarandarguesthat
thiswasaresultofcollaborationwithintheTherapeuticResearchCommittee,involving
severalfirms,andthevictoryofpenicillin.Oncemorethisconclusionarisesfromthe
focusonmajordevelopments(inthiscasepenicillin)andanacceptancethatlittlewas
achievedintheinterwarperiod.Andyetthereisaremarkablecontrastbetweentheposition
oftheBritishindustryin1938,preparingtomakedrugsthatmightberequiredforwar,
comparedtothestarkrealisationattheoutbreakoftheFirstWorldWarthatBritainrelied
soheavilyonGermany,notonlyfordrugsbutforthechemicalintermediatesrequiredto
36
D.ChapmanHustonandE.C.Cripps,(1954)R.P.T.DavenportHinesandJ.
Slinn,(1992)GeoffreyTweedale,(1990)JudySlinn(1984)E.M.Tansey,(1989):141.37
38
M.Robson,(1988):94.
M.Robson,ThePharmaceuticalIndustryinBritainandFrance19191939(Dept.of
EconomicHistory,LondonSchoolofEconomics:PhD.thesis,June1988)J.Sigvard,
DrugIndustryinFrance:SomeHistoricalPointsBull.Acad.Natl.Med.
166(June 1982):82934.
23
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
24
makethem.ExaminingtheFirstWarinisolationisinsufficientasitwasanartificial
situationwithdisruptionoftradeandtheabsenceofacompetitivethreatfromGermany.
Oneofthemainchallengeswastoproducedrugsonalargescaleandcosteffectivelyto
competewithGermany afterthewar.
Syntheticdrugsarethemainstayofthemodernpharmaceuticalindustry,butthe
molecularmanipulationthatgaverisetonewdrugsbeganinGermanyattheendofthe
nineteenthcentury,andGermanyheldamonopolyinsyntheticdrugspriortotheFirst
WorldWar,withdrugssuchasSalvarsan,NovocaineandAspirin.Asaresulttherehas
beenadearthofinterestinthisaspectofthedevelopmentofthepharmaceuticalindustry
outsidetheGermaniccountriesandanassumptionthatAmericaandBritaineventually
followedtheGermanmodel.Iwilldiscusshowthiswasnotalwaysthecase,atleastuntil
after1939.
SwannmadeonlypassingreferencetothefactthatEliLillyestablishedaresearch
teamonsyntheticdrugsin1912,involvingupto20researchershedidnotexplainwhere
theycamefromorwhethertheydidevolvefromassaywork.HedescribedhowAbbott
firstdevelopedsyntheticdrugs,butasaresultofexternalcollaboration,andthenby
employingapostdoctoralstudentin1918.BeyerdescribedhowDilantin(phenytoin)was
firstsynthesisedatParkeDavisin1911,buthedidnotdescribetheinitialevaluation
only
pointingoutthatitshypnoticeffectswereonlyfoundaspartofaroutinescreenin1926
anditsbenefitsinepilepsywerenotdescribeduntil10yearslater:hestatedthatParke39
DavisdidnotformallyestablishaChemistrydepartmentuntilthe1920s.
IntheGreatWar,America,likeBritainwasdeniedGermandrugs,initiallyasaresult
ofnavalblockade.The1916versionofNewandNonOfficialRemedieslisted228of
592drugsascomingfromGermany.AftertheUSAdeclaredwarinApril1917,some
GermanpatentswereabrogatedandAmerica,likeBritain,hadaTradingwiththeEnemy
Act,andyetSwannsuggestedthat:U.S.pharmaceuticalfirmssoonfilledthedemandfor
these(synthetic)drugs.However,elsewhereinhisbookSwanndemonstratedthatitwas
onlyafterthewarinmostAmericanfirmsthatinternalresearchfacilitieswereestablished,
initiallyappointingexternalscientists,notablyatAbbott(1918),Lilly(1919),ParkeDavis39
KarlH.Beyer,Discovery,DevelopmentandDeliveryofNewDrugs(NewYork:S.P.
MedicalandScientificBooks,1978):43.
24
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
25
(1920),andMerck(1930),althoughUpjohnandSquibbappointedtheirfirstresearch
scientistsin1913and1915respectively.ItremainsunclearhowAmericanpharmaceutical
firmsfirstestablishedsyntheticdrugsynthesisandnothinghasbeenwrittenon
manufacturingcapacity.Certainlyseveralfirmscontinuedtodependonexternal
collaborationsfordiscoveriesandthisseemstobeastrongfeatureoftheAmerican40
industry.
LiebenauaddressedtheproductionofSalvarsanbytheDermatologicalResearch
LaboratoriesinChapter8ofhisbookMedicalScienceandMedicalIndustry.Robson
brieflyaddressedtheproblemsofwartimedrugshortages:ItwastheFirstWorldWarthat
disturbedthestatusquoandmarkedtheturningpointforthestandingofsciencewithinthe
pharmaceuticalindustry.However,heconcludedthattherewerenoimmediate
shortagesasaresultofthedislocationoftrade,withoutgoingintodetailabouthowthe41
essentialdrugsweredefined,manufacturedortested.
Thiscontrastswithmyfindingthat
BritainwasheavilyreliantonGermany
forsyntheticdrugsandcertainalkaloids.
BothRobsonandQuirketoadegreerefertosomeofthestaffmobilitybetweenthe
MRCandindustry,withRobsonmakingabriefreferencetoFrancisCarrandhisdeparture
fromBurroughsWellcome.However,Carrsrolewasperhapsnotfullyunderstoodby
QuirkewhobrieflydescribedhimasbeingtakenonbyBDHtoproduceinsulin,whereasit
washisestablishmentofthemanufacturingcapacityofBDHintheperiod192022that
madetheinsulindevelopmentthesuccessthatitwas.SimilarlyIdidnotfollowQuirkes
argumentthatafocusonantiserapreventedtheearlierexploitationofpenicillinin
Britain.ShearguedthatFlemingwasobsessedwithdemonstratingthatpenicillincouldbe
usedasaselectiveinhibitorofbacterialgrowthandspecificallyamethodtoisolate
Haemophilusinfluenzae,andthatthistiedinwiththeinfluenceofAlmrothWrightin
promotingvaccines,includingoneforinfluenza.
AmoreobviousexplanationisthatneitherFleming,northemanyothersthat
investigatedpenicillininthenext14yearscouldenvisageamethodoflargescale
productionandthisseparatesaninterestinglaboratoryphenomenonfromapracticaldrug.
4041
JohnP.Swann,(1988):356. M.Robson,(1988):82105.
25
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
26
Iteventuallytookamassiveinternationalefforttodeveloppenicillinandthiswasonly
stimulatedbythewartimeneedsandfollowingthesuccessofthesulphonamides.Nonew
drugisusefulunlessitcanbemanufacturedreliablyandpartofthechallengeforBritainin
thisinterwarperiodwastoencouragethetrainingofchemicalengineersandmanufacturing
chemiststomakethispossible.
However,detailsasideQuirkeprovidesavaluablecomparisonofBritainandFrance,
inwhichshecontraststhecentralcoordinatingrolesofthePasteurInstituteandtheMRC
forwhichsheidentifiedtheimportantroleofDaleinbreakingdownthebarriersbetween
industryandacademia,thoughasIwillshowbarriersstillexistedtogettingclinicaltrials
performed. 1.3ClinicalTestingofNovelDrugs.
Stilllessattentionhasbeengiventotheoriginsofclinicaltrialsofnewdrugsfrom
industry.Someauthorshavechartedancienttrialsorthedevelopmentofmeasurement42
inmedicine.
Thehistoriographysuggeststhatnumericalmethodsofassessmentin
medicinespreadfrom
ParisatthestartofthenineteenthcenturyandTroehlerexamined43
thisinathesis,whichfocussedonthetechniquesandthescopeofdatacollected.
His
thesisisanexcellentinitialsourceforanunderstandingofthedevelopmentofthenumerical
accountinmedicine,offeringaseriesofindividualexamplesofwellrecordedproperly
recordedobservations,startingwithJamesLindandcollectionsofstatisticsintheNavy
onscurvyin1763,ratherthanaclearpathofinfluences.Heshowsthatthereweremany
earlyexamplesoflargewellcontrolledstudies,andyetthemethodswereintermittently
adopted.JohnFerriar,aManchesterphysician,wrotein1792thatthetendencyso42
J.P.Bull,TheHistoricalDevelopmentofClinicalTherapeuticTrialsJournalof
ChronicDiseases10(1959):218248H.J.C.J.L'Etang,HistoricalAspectsofDrug
EvaluationinE.L.Harris,J.D.Fitzgerald(eds.),PrinciplesandPracticeofClinical
Trials.(Edinburgh:ChurchillLivingstone,1970)JanP.Vandenbroucke,AShortNote
ontheHistoryoftheRandomisedControlledTrialJournalofChronicDiseases40(1987):
985987A.M.Lilienfeld,CeterisParibus:theEvolutionoftheClinicalTrialsBulletin
oftheHistoryofMedicine56(1982):118U.Troehler,QuantificationinBritish
MedicineandSurgery,17501830withSpecialReferencetoitsIntroductioninto
Therapeutics(UniversityofLondon:PhDthesis,1978).43
ErwinAckerknecht,MedicineattheParisHospital17941848(Baltimore:Johns
th Hopkins,1967)J.P.Vandenbrouke,ClinicalInvestigationinthe20
Century:the
AscendancyofNumericalReasoningTheLancet(October1998)Sii:1216.
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
AbrahamFlexners1910reportIwilldescribeparallelstothesystemdevelopedbythe44
MRCinBritain.
HarryMarksexaminedtheestablishmentofcooperativeclinicaltrialsin
America,emphasisingthatotherformsoftherapeutictrialspredatedrandomised45
controlledtrials.
Heexaminedhowtherapeuticdecisionsweremadeandemphasisedthe
roleoftheAmericanMedicalAssociationsCouncilonPharmacyandTherapeuticsandof
academicresearchcentreswithintheNationalResearchCouncilsDivisionofMedical
Science.Hecautionedagainsttakingapurelymethodologicalapproach,astherewasmore
tochangingviewsontherapeuticsthanthedesignoftheexperiments.Cliniciansdeferredto
moreknowledgeableexpertsandpartoftherationaleforcollaborativetrialswastoengage
44
AbrahamFlexner,MedicalEducationintheUnitedStatesandCanada(NewYork:
CarnegieFoundation,1910).45
HarryM.Marks,IdeasasSocialReforms:TheLegaciesofRandomizedClinicalTrials
(PhDThesis,HarvardMedicalSchool,1983)HarryM.Marks,TheProgressof
Experiment:ScienceandTherapeuticReformintheUnitedStates,19001990(Cambridge:
UniversityPress,2000).
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.GeraldGeisondescribedthisin46
Dividedwestand andSwannreferredtolongstandingconflictsbetween
laboratory
workersandclinicians.Mostofthehistoricresearchonthepharmaceuticalindustryhas
focussedondrugdiscovery,tellinguswhatwasdiscoveredandwhen,andwithlittleon
drugdevelopment.
Thedevelopmentphasethathasevolvedsincenoveldrugswerepreparedwas
initiallyasimpleprocess,buthasbecomeincreasinglycomplexitinvolvesturninganewly
discovereddrugintoamedicinethatcanbeprescribedsafelytopatients.Itinvolves
selectingthedose,formulatingthedrugasaninjection,tabletorsomeotherform,and
testingitfirstinanimalsandtheninpatients,producingdatatoencourageotherdoctors
totrythedrugandultimatelytomakeitacommercialsuccess.Anotherpartofdrug
developmentoperatesatastrategiclevelandconcernsdecisionsregarding,whichdrugsto
developandwhatresourcesandfacilitiesarerequiredtosupporteachpotentialdrug.This
phaseofdrugdevelopmenthasreceivedlimitedattentionandIexploredthisthroughthe
internalrecordsoftheBurroughsWellcomeScientificandTechnicalCommittee,andbased
onmyownconclusionsofwhatothercompaniesproducedandhadtestedbythe
TherapeuticTrialsCommittee.
46
G.L.Geison,DividedWeStand:PhysiologistsandCliniciansintheAmerican
Contextin
M.J.VogelandC.E.Rosenberg,TheTherapeuticRevolution:Essaysinthe
SocialHistoryofAmericanMedicine(Philadelphia:UniversityofPennsylvaniaPress,
1979).
28
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
29
LiebenauconcludedthattheMRCstudiesoninsulinformedthemodelforfuture
collaborativeresearch,andbothQuirkeandRobsonreferredtohisseminalwork.Thus,
onthebasisofalimitedappraisalaviewhasbeenperpetuatedthatthiswasafoundation
modeluponwhichtheMRCrefinedstudydesignsandadrugdevelopmentprocess
culminatinginthefirsteverrandomisedcontrolledtrialofstreptomycinin1946.Toa
degreethishasbeenfuelledbythewritingsofmanyoftheparticipantsinthoselater47
trials.
Theconclusionthatasystemofclinicaltrialswasmodelledonthoseforinsulinand
thattheMRCbuiltuponthisinanefforttocontroltheindustryhasnotbeenchallenged
sinceLiebenausaccountinwhichhereferredmistakenlytoinsulinasapituitaryhormone.48
BoothexaminedthegrowthofMRCsponsoredclinicalresearchcentres,butonlyby
49 referringtoMRCannualreports.
Wastheinsulinmodelrepresentativeofotherstudies
performedbytheMRCintheperiodupto1946oristhismodelonlyapplicabletothe
developmentofproductswheretheMRCheldthepatentandcouldcontrolthe
collaborators?Intheirrecenttheses,bothDesireCoxMaksimovandthenVivianeQuirke
tookinsulinastheacceptedmodel.Theimpressionisgivenintheseaccountsthatdrugs
simplycameintogeneraluse,asifitwereobviousthatdrugsthatworkedinthelaboratory
wouldbeefficaciousandsafeinman.Thismayhavebeenthecaseforinsulinandpenicillin,
regardingtheirspectacularactivity,butthisfocusonmajorsuccessesgivesnoinsightinto
theroutineresearchfornovel
drugsthatwasthebreadandbutterofthepharmaceutical
industry.Whataboutthosedrugsthatdidnotworkorcausedadverseeffects?The
forefrontofthisresearchwasintheclinic.Evenattheendofthenineteenthcentury,
Ehrlichrecognisedthattheonlytruetestofadrugwasinmanandcompaniesusedtheir
earlyexperienceinpatientstomodifytheirproducts,toevaluatenewdosageforms,to
47
J.Liebenau,TheMRCandthePharmaceuticalIndustry:theModelofInsulinin
JoanAustokerandLindaBryder(eds.),HistoricalPerspectivesontheRoleoftheMRC
(OxfordUniversityPress,1989):163180.48
J.Liebenau,TheMRCandthePharmaceuticalIndustry:theModelofInsulin
(1989):169.49
C.C.Booth,ClinicalResearchinJ.Austoker,L.Bryder(eds.)Historical
PerspectivesontheRoleoftheMRC.(Oxford:OxfordUniversityPress,1989):205241.
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
modelthatemergedfromtheearlierChemotherapyCommitteeforrandomisedcontrolled51
trials.
Herstudywascarriedoutinparallelwithmyownresearchandcoversmyperiod
ofinterest.BecauseshealsoexaminedtheTTC,herthesisbearstheclosestparallelsto
mineandthereforedeservescloseattention.Inaseriesofcasestudiesshecontrastedthe
effortsofpatentmedicinemanufacturerswiththescientificapproachesofthemedical
establishmentandtheState,whichsupportedthemoreacceptablestandardisedmedicines52
evaluatedbytheMRC.
Sheexaminedtrialsofinsulinfordiabetes,trialsofpneumococcal 53
serum,andpatulinforthecommoncold.
Thus,herapproachwasverydifferent,ignoringtheproductsarisingfrom
pharmaceuticalindustryresearchandconcentratingonthemethodologyofthelargertrials54
ratherthantheprinciplesoftestingnewagents.
Patulin,likeinsulinwasanaturalproduct
50 51
VivianeQuirke,(UniversityofLondon:PhDthesis,1999).
D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945.
Expertise,theStateandthePublic(Cambridge:PhD.Thesis,September1997):17130.52
D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945.
Expertise,theStateandthePublic(Cambridge:PhD.Thesis,September1997):17130.53
54
D.CoxMaksimov,(1997):183262. Ibid..
30
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
31
55 arisingfromacademicresearch
ratherthanadrugfromindustryandthepatulinstudies
wereusedtodescribethemechanisationoftrialsandthekeyroleofthestatistician,Major56
Greenwood,whohadbeeninvolvedinclinicaltrialdesignformanyyears.
TheMRC
werebecomingarbitersofdrugevaluation,determininghowmedicalresearchwas
reported,thecharacterisationandstandardisationofmedicines,therecognitionand
authorityofexperts,howtheresearchwasreportedeventhecentresinvolved.
AccordingtoCoxMaksimov,theTTCwasaboutpromotingacertaintypeof
medicalresearch,butwasitreally?My
argumentisthatbyselectingonlythewinning
drugssuchasinsulinhistoriansmayhaveintroducedabias.Quirkealsoevaluatedthe
impactoftheinsulinclinicalstudiesandconcluded,likeLiebenau,thattheseformedthe
modelforallfuturetrialsandcollaborationswithindustry.Liebenau,QuirkeandCox
Maksikovdonotaddresstheissueofmanufacturinginsulinorwhowasinvolved.Innot
doingsotheymissedtheimportantlinkthatFrancisCarr,whohadpreparedSalvarsanat
BurroughsWellcome,hadmovedfirsttoBootsthentoBritishDrugHouseswherehe
establishedthecapacitytomanufacture95%ofBritishrequirementsforinsulin.Carr,
amongothersledtherequestsfromindustryforasystemofclinicaltestingofnewdrugs
andthecompaniesatthetimeclearlydidnotseeinsulintrialsasamodeltomeettheir
needs.
Thetrialofpneumococcalserumwasnotatallrepresentativeofthemainworkof
theTTCasitwasalreadyplannedin1929,twoyearsbeforetheestablishmentoftheTTC
in
1931.Furthermorethestudyaddressedquestionsabouttheneedtovaccinaterather
thanbeingastudyofnewdrugs,andfurthermore,initialvaccinesuppliescamefrom
America. CoxMaksimovexaminedinturnhowalloftheproceduralelementsof
the
randomisedclinicaltrialwereinplaceby1946andarguedthatthepneumococcaltrial
definedprocedures.Iamnotconvincedthatthepneumococcalstudywasthemajor
influencethatshesuggestsandwithoutintendingtoclaimanincreasedvalidityof
afirst55
H.Raistrick(firstofseveralpresentations),PatulinintheCommonCold.
CollaborativeResearchonaDerivativeofPenicilliumpatulumBainierLancet
(20 November1943):62534.56
L.Hogben,MajorGreenwoodBiographicalMemoirsofFellowsoftheRoyalSociety
7(1950):13954.
31
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
32
handsource,herinterpretationconflictswiththeaccountrecalledtomebySirAustin
BradfordHill,thefounderoftherandomisedcontrolledtrialandbyhissurviving57
colleagues.
Therewerequitedifferentobjectivesandalsoethicalconstraintsin
vaccinatingindividualsagainstthepossibilityofacquiringacommondiseasecompared
withtreatingthemwithanovelchemicaltotreatadiseasealreadypresentandparticularly
regardingwithholdingtherapyintheplacebogroup.CoxMaksimovmadetheimportant
pointthatrecentaccountshavebeenwinnershistoriesofClinicalTrials,oneinwhich58
statisticianssuchasPeterArmitage ,RichardDoll,59
RichardPetoandSirAustin
BradfordHilldominateandclaimownershipofclinicaltrials.Theirargumentsconcernthe
qualityofthedesignofexperiments,theremovalofsourcesofbias,andacertainwayof
reportingdataandinthisrespecttheirauthoritycannotbequestioned,butwasthislater
modelofrelevanceinthe1930s?CoxMaksimovarguedforanaturalprogression
throughtheTTCpneumococcalstudy,theMRCstreptomycinstudies,andpatulin60
studies,
arguingthatArmitagehadreferredtoBradfordHillhavingaroleintheTTC,
thoughsherecognisedtherewasnodocumentaryevidenceandIfoundlittleeitherthefirst61
referencetohimwashisattendanceatthetenthcommitteemeetingin1939.
Lilienfeld
tookanalmostgenealogicalapproachandtriedtotracethecontrolledtrialslinkback
furthertostudiesofthegoldtherapy,sanocrysinin1925,andothershavealsoarguedthat
57
LettertomyselffromSirAustinBradfordHill(6October1988)P.DArcyHart,
EarlyControlledTrialsBritishMedicalJournal
312(10February1996):37879A.
BradfordHill,MeasurementinMedicine:TheClinicalTrialBrit.Med.Bull.7.4(1951):
27882A.BradfordHill,TheClinicalTrialNewEnglandJ.Med.247(1952):113P.
Armitage,BradfordHillandtheRandomisedControlledTrialPharmaceuticalMedicine6
(1992):2337R.Doll,SirAustinBradfordHillandtheProgressofMedicalScience
BritishMedicalJournal
305(1926December1992):152126I.Chalmers,M.Clarke,J.
G.Scadding,inI.Chalmers,I.Milne,U.Troehler(eds.),TheJamesLindLibrary(
www.jameslindlibrary.org)accessed7January2003.58
P.ArmitageisEmeritusProfessorofAppliedStatisticsattheUniversityofOxford:P.
Armitage,(1992):2337.59 60
RichardDoll,(1992):152126.
J.M.Stansfield,A.E.Francis,C.H.StuartHarris,LaboratoryandClinicalTrialsof
Patulin:MedicalResearchCouncil,ClinicalTrialofPatulinintheCommonCold(16
September1944)Lancet:37375.61
BradfordHillwasonlyappointedtotheTTCforthetenthandfinalmeetingin1939:
TTCMinutes10,(28March1939),MRCFile1523/15(TTC).
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.B.E.C.Gill,RandomisedMentalHealthTrialBeganin1935andM.Clarke.
QuasirandomAllocationofTreatmentwasReportedin1930,bothin
BritishMedical Journal
312(18May1996):1298A.M.Lilienfeld,Ceterisparibis,theEvolutionofthe
ClinicalTrial. BulletinoftheHistoryofMedicine56(1982):118.63 64
D.CoxMaksimov,(1997):21. D.CoxMaksimov,(1997):21.
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
PietroCorsi,P.Weindling,InformationSourcesintheHistoryofScienceand
Medicine(London:Butterworth,1983)P.Weindling,ResearchMethodsandSourcesin
E.Clarke(ed.),ModernMethodsintheHistoryofMedicine(London:Athlone,1971):
173.
34
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
35
66 theideaofGovernmentshapingindustryhastakenroot.
Amajoremphasisisplacedon
67
theroleofsignificantindividuals,andparticularlyFrancisCarr.
TheearlypartofthethesisaddressesthedominanceofGermanchemistrywithina
researchorientedindustry.Dyestuffsandchemicalintermediateswereprimarilyimported
fromGermany.Universitybasedchemists,manyofwhomwereconsultantstoindustrial
firms,hadwarnedbeforetheFirstWorldWaraboutthefactorsleadingtothedominance68
ofGermany.
AgeneralthemethroughoutistheshortageofsuitablytrainedBritish
chemists,particularlythosewithmanufacturingexperience.Manyofthechemicalprocesses
dovetailedintoeachotherandthemanycomplexinterdependenciesbetweenfirmsreliedon
chemicalintermediates.LittlepreparationwasmadefortheoutbreakofWaranditis
interestingtocontrasthowbetterpreparedBritainwasbetween19371939andhowmuch
thecountrydependedontheinterwarefforts.
ThethemesthatemergethereforeareofsustainedeffortstoensurethatBritainnever
againhadtorelyonaforeignpowerforkeyresources.Thisinvolveddefiningwhatdrugs
wereessential,whomadethem,whatchemicalintermediatesandsolventswereneeded,
howthedrugscouldbestandardisedandhowtheirpotencycouldbemeasured.
Additionallythesyntheticarsenicaldrugs,replacingthosehithertoonlymadeinGermany,
werepotentiallytoxicandhadtobeshowntobesafeandeffective.
TheMRCtookacentralroleintheevaluationof
Salvarsanbutmanyoftheirstaff
camefromindustryandparticularlyBurroughsWellcome.Giventhescarcityofchemists,
pharmacologists,physicianresearchersandotherkeymembersofstaff,itisinterestingto
charttheircareerstoseetheeffectthattheyhadonthedevelopmentofseveralBritish
pharmaceuticalfirms.TheMRCandgovernmentcontinuedtosupporttheBritishindustry
throughouttheperiodunderstudy,andanotherthemewhichemergesistheeffortmadeto
protecttheevolvingresearchbasedBritishpharmaceuticalindustry,firstlyunderthe
66
EricMoonman,ReluctantPartnerships:aCriticalStudyoftheRelationshipBetween
GovernmentandIndustry (London:VictorGollanez,1971):17.67
JosephBenDavid,TheScientistsRoleinSociety
(EnglewoodCliffs:PrenticeHill, 1979):16068.68
W.M.Gardner,TheBritishCoalTarIndustry,ItsOrigin,DevelopmentandDecline
(London:Williams&Norgate,1915).
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,companiesbegantoemploytheirownpharmacistsand69
physicianstoestablishtheclinicaltestingofdrugs,
andthistrendevenbeganinthelate
1930s.
Despitethebroadchronologyofthethesis,inevitablytherearesomeslightoverlaps
betweensections.ForexampleitseemedsensibletoincludealloftheWaractivities,
includingproductionandtestingofSalvarsaninonechapter,soIalsoincludedthework
thatcontinuedonSalvarsanafter1918asitinvolvedthesameindividuals.
FollowingonfromthisIntroduction,Chapter2describesthevariedoriginsofthe
Pharmaceuticalindustryin
thenineteenthcenturyandassessesthepositionofthesmall
Britishcompaniesinrelationtotheirlargerinternationalrivals,contrastingtheethical
manufacturerswithproducersofpatentmedicines.
69
K.J.Williams,B.Gennery,TheHistoryofthePharmaceuticalIndustryinJ.Lloyd,
A.Raven(eds.),HandbookofClinicalResearch
(London:Churchill,1994):122K.
Williams,ATenthAnniversaryfortheAssociationforClinicalResearchinthe
PharmaceuticalIndustry(ACRPi)PharmaceuticalMedicine3(1988):219224.
37
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
38
Chapter3describesthemostresearchorientedBritishfirm,BurroughsWellcome,
andhowtheycombinedthebestofGermansyntheticchemistrywithAmericanadvancesin
drugformulation,especiallytablets.ItwastheonlyBritishfirminitiallyinapositionto
rapidlytakeupthesynthesisofthemorecomplexGermandrugsandtodevelopthestrong
linkswiththenewlyfoundedMRC.Iintroduceindividualswhoweretoplayanimportant
roleinthedevelopmentandtestingofdrugsthroughouttheinterwarperiodof191970
1931.
Chapter4examineshowtheFirstWorldWarforcedtheBritishGovernmentto
interveneinpharmaceuticals,firstbyestablishingcommitteestoestablishwhichdrugswere
essentialandthenhowtoresolvetheirproduction.IexaminehowBritishfirmsbeganto
collaborateformallyforthefirsttimeastheAssociationofBritishChemicalManufacturers,
howBritishfirmsmasteredlargescalechemicalsynthesis,andhowtheMRCfirstgot
involvedintestingSalvarsanasanextensionofthestandardisationworkcarriedoutbyits
staff whentheywereatBurroughsWellcome.
Thenfollow3chaptersthatbroadlycoverthesameperiod:
Chapter5coverstwoaspectsofpostwarBritain.ItexamineshowBritish
pharmaceuticalfirmssoughtprotectionpostwar,firstbytariffs,thenbystandardisationof
biologicalandhormonalextracts.TheMRCassistedandindoingsoestablishedtheir
internationalreputationfordrugstandardisation,whileextendingtheirinterestinclinical
outcomes.
Chapter6describeshowBritishfirmscampaignedforclinicaltestingofdrugsfrom
19221930anddemonstrateshowtheMRCwasanidealintermediarybetweenthefirms
andresearcherstoestablishgroundrulesforearlyclinicaltrialsinBritain.Thespecialised
MRCsubcommitteesandtheChemotherapyCommitteedidnotmeettheneedsofthe
pharmaceuticalcompaniesandIdemonstratethedistinctionbetweenMRCresearchto
supportindustryandtheirownmoreacademicallyorientedstudiesandtheutilisationof
theiremergingnetworkofclinicalcentres.
70
FrancisJ.Griffin,Obituary,FrancisCarrChemistryandIndustry
(15February 1969):196.
38
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.
Earlynineteenthcenturydrugtherapywasaimedatalleviatingsymptomssuchas1
feverandpain.
By1900twoparallelbutoverlappingsystemsofdrugmarketinghad
evolvedinallofthemainmanufacturingcountries.Patentmedicineshadbeenavailable2
forovertwocenturies,buttheiruseexpandeddramaticallyduringthenineteenthcentury.
Theywerepreparationswhoseingredientswerekeptsecret,andwhichweresoldunder3
brandnamesforawiderangeofillnesses.
Theirsuccessdependeduponheavy
advertisinginthepopularpress,andthefactthattheysparedpatientstheexpenseofa
doctor'sconsultationfee.Patentmedicineswereofvariablequality,wereoftenlacedwith
opiatesoralcohol,oronlyincorporatedminutequantitiesofwhatdoctorsandpharmacists
consideredactivedrugs.Doctorswereconcernedthattheywereineffectiveandeven4
potentiallydangerous.
Ethicalmanufacturerstookadifferentapproach.Theidentification,extraction,and
purificationofmorphineinParisin1803stimulatedtheestablishmentofseveralalkaloid
manufacturingfirmsinFrance,followedbyBoehringer,Merck,andScheringin1
A.Burman,TheHeroicApproachtoNineteenthCenturyTherapeuticsBulletinof
theAmericanSocietyofHospitalPharmacists11(1954):32027DavidL.Dykstra,The
MedicalProfessionandPatentandProprietaryMedicinesDuringtheNineteenthCentury
BulletinfortheHistoryof Medicine29(1955):40119.2
PatentMedicineTaxReceipts18291914Chemist&Druggist85.1(8August
1914):3536T.Hughes,ThePatentMedicineStampDuty:itsOriginandHistory
BritishMedicalJournal
(9January1932):3233RevenuefromPatentMedicineTax
Stamps18001931Chemist&Druggist114(30May1931):639.3
V.Coleman,TheMedicineMen
(London:TempleSmith,1975)B.McNamara,Step
RightUp:anIllustratedHistoryoftheAmericanMedicineShow(NewYork:Doubleday
&Co.,1976)RoyPorter,
Quacks,FakesandCharlatansinEnglishMedicine(Charleston:
Tempus,2001)WilliamH.Helfand,TheSellersofNostrumsinPrints,Posters,Ephemera
andBooks(Chicago:ChicagoUniversityPress,2002).4
JamesH.Young,
TheToadstoolMillionaires:aSocialHistoryofPatentMedicinesin
AmericaBeforeFederalRegulationinAmerica16601850(Princeton:Princeton
UniversityPress,1961)JamesH.Young,TheMedicalMessiahs:aSocialHistoryof
HealthQuackeryinTwentiethCenturyAmerica(Princeton:PrincetonUniversityPress,
1967)M.Silverman,MagicinaBottle(NewYork:McMillan,1941)M.Silverman,The
DruggingoftheAmericas(Berkeley:UniversityofCaliforniaPress,1976).
40
TheOriginsofthePharmaceuticalIndustry
41
5 Germany.
Suchmanufacturersdifferentiatedthemselvesfurtherbyproducingthenewly
6 discoveredchemicalelementsbromineandiodine,inrichsupplyinGermany.
Luke7
HowardinLondonproducedcalcinedmagnesium,bismuthandmercurysaltsfrom1801.
MorsonsandHowardssoldquininesulphateinsteadofcinchonafrom1821,andfirms
wereabletocomparethebestsourcesofquinine.From1827firmssuchasMercksold8
purifiedmorphine,insteadofopium,asdidT.H.SmithinEdinburghby1837.
Firms
manufacturedplantextractsandinorganicremediesaccordingtothedemandsof9
physicians.
Inotherwords,doctorsdecidedwhichdrugswereneededandpharmaceutical
manufacturersprovidedthem.
Somedoctorsproducedtheirownmedicines,butasextractionofalkaloidsbecame
morecomplex,requiringsolvents,distillationandcrystallisation,manufacturerssaved
themtheexpenseofpurchasingmachinery.Ascapacityincreased,standardpackswere
preparedanddistributedwidelyfortreatingstandardandspecificdiseases.Manyfirms
producedthesamebasicdrugs,butindividualfirmsdistinguishedtheirdrugsfrom
competitorsbyassayingchemicalconstituentsandimpuritiesinsimplelaboratorytests.
5
M.Weatherall,InSearchofaCure:aHistoryofPharmaceuticalDiscovery
(Oxford: OxfordUniversityPress,1990)WalterSneader,
DrugDiscovery:theEvolutionof
ModernMedicines(London:JohnWiley,1985):67,914C.D.Leake,AnHistorical
AccountofPharmacologytotheTwentiethCentury
(Springfield,Illinois:C.C.Thomas,
1975):1201JohnHarleyWarner,TheTherapeuticPerspective:MedicalPractice,
KnowledgeandIdentityinAmerica18201885(Cambridge,Massachusetts:Harvard
UniversityPress,1986)
E.MerckofDarmstadt:aHistoryofChemicalAchievement
18271937(Darmstadt:Merck,1937).67
WalterSneader,(1985):4142. D.L.Howard,
Brit.Col.Pharmacist(August1926):241.
8
W.Bernsmann,ArzneimittelforschungundEntwicklunginDeutschlandinder
ZweitenHlftedes19JahrhundertsPharmazeutischeIndustrie29(1967):6Mark
Honigsbaum,TheFeverTrail:TheHuntfortheCureforMalaria(London:MacMillan,
2001).9
E.Kremers,G.Urdang,TheHistoryofPharmacy
(Philadelphia:J.B.Lippincott,
4thedition,1976)R.D.Mann,ModernDrugUse,anEnquiryonHistoricalPrinciples
(Boston:MTPPress,1984)F.N.L.Poynter,TheEvolutionofPharmacy (London:
PitmanMedical,1965):13149E.H.Ackerknecht,
TherapeuticsFromthePrimitivesto theTwentiethCentury
(NewYork:Hafner,1973):8889JonathanLiebenau,TheRise
oftheBritishPharmaceuticalIndustryBritishMedicalJournal
(3October1990):72428, 733.
41
TheOriginsofthePharmaceuticalIndustry
42
Thepurityofdrugsproducedbyreputablefirmsimprovedastheirpharmacistsadopteda10
moreprofessionalrole.
JacobBellofJohnBell&Co.wasoneofthefoundersofThePharmaceutical11
SocietyofBritainin1841andwasPresident18569.
WilliamAllenofAllen&
12 Hanburyswasthefirstpresident.
TheSocietywasmodelleduponthePhiladelphia 13
CollegeofPharmacy,foundedinAmericain1821.
WhereasFrenchfirmsmade
referencetoexperimentsinanimalsbyphysiologistssuchasFrancoisMagendieand
ClaudeBernard,andGermansreferredtoEmil
Fischer,HermannKolbeandothers,such
assayswerecontinuouslyhamperedinBritainbytheantivivisectionlobbyfromthe1860s
andthisinhibitedthedevelopmentofpharmacologyandinteractionsbetweenthe14
pharmaceuticalindustryandexternalacademicsinBritain.
Bythecloseofthe
nineteenthcentury,theBritishpharmaceuticalindustrywasstrugglingtokeepupwithits15
counterpartsinGermanyandinAmerica.
Pharmaceuticalsevolvedonalargescalein
Germany,whereasAmericanfirmsmadesignificantadvancesinnovelmeansof
administeringdrugs.AnappreciationofthecompetitionfacedbyBritishfirmswillenable
ustounderstandmuchaboutthewaysinwhichasectionoftheBritishpharmaceutical
10
J.K.Crellin,TheGrowthofProfessionalisationinNineteenthCenturyBritish
PharmacyMedicalHistory
11(1967):215227F.A.Filby,AHistoryofAdulteration
andAnalysis(London:GeorgeAllen&Unwin,1934)E.W.Stieb,G.A.Sonnedecker,
DrugAdulteration,DetectionandControlin19thCenturyBritain
(Madison:Universityof
WisconsinPress,1966)J.A.Blake(ed.),(1970).11
JohnBellaComingCentenaryChemist&Druggist52(11June1898):1605S.
W.F.Holloway,RoyalPharmaceuticalSocietyofGreatBritain18411991:APolitical
andSocialHistory
(London:ThePharmaceuticalPress,1991):appendix.12
L.G.Matthews,HistoryofPharmacyinBritain
(EdinburghandLondon:E.&S.
Livingstone,1962):11827L.G.Matthews,AnUnrecordedWilliamAllenCaricature
MedicalHistory 15(1971):3056.13
J.W.England(ed.),
TheFirstCenturyofthePhiladelphiaCollegeofPharmacy
18211921(Philadelphia:PhiladelphiaCollegeofPharmacy,1922).14
J.M.D.Olmsted,FrancoisMagendie(NewYork:Schumanns,1944)Claude
Bernard,AnIntroductiontotheStudyofExperimentalMedicineTrans.H.C.Greene,
(NewYork:Dover,1957)R.D.French,AntiVivisectionandMedicalSciencein
VictorianSociety (Princeton:PrincetonUniversityPress,1975).15
J.T.Mahoney,Merchantsof
Life:AnAccountoftheAmericanPharmaceutical Industry
(NewYork:Harper,1959).
42
TheOriginsofthePharmaceuticalIndustry
43
industryadaptedandmadeuseoflaboratoryscienceasameansofdevelopingand16
marketingcompetitivenewproductsinthe1880s.
2.2EvolutionfromSmallPharmacyFirmsinAmerica.
IntheearlynineteenthcenturymostmedicinesusedintheUSAwereimported
fromBritain.PhiladelphiabecamethecradleofpharmacyfortheAmericannation,
famousfortheCollegeofPharmacyfoundedin1821,aroundwhichanAmerican
pharmaceuticalindustrywasestablished.EarlygraduatesoftheCollegesuchasErnstR.17
Squibbattackedthefraudulenceandadulterationassociatedwithpatentmedicines.
Philadelphiabasedfirmscreatedandeffectivelycontrolledalucrativenewsector18
ofthepharmaceuticalmarket,ethicaldrugssoldsolelytomedicalprofessionals.
The
termethicalmedicinecameintousein
theUSAafterthe1847codeofethicsofthe
AmericanMedicalAssociationforbadedoctorsfromprocuringapatentforaremedy,and19
fromsellingpatentmedicinesornostrums,orgivingtestimonials.
AsinBritain,there20
wasahugemarketfortheseremedies,oftensoldwithfancynames.
The1877byelaws
ofthePhiladelphiasectionoftheAmericanMedicalAssociationstated:
Anyphysicianwhoshallprocureapatentforaremedyorforany
instrumentofsurgery,orwhosellsorisinterestedinthesaleofpatent
remediesornostrums,orshallgiveacertificateinfavourofapatentor
proprietaryremedyorpatentedinstrument,orwhoshallenterintoagreement16
ThePharmaceuticalIndustry'tovaryingdegreesincluded'theChemicalandAllied
Trades'and'theFineChemicalIndustry':WhatisaFineChemicalChemist&Druggist
85.2(29August1914):51.17
L.G.Blochman,DoctorSquibb:TheLifeandTimesofaRuggedIdealist(New
York:Simon&Shuster,1958)J.T.Mahoney,Philadelphia,CradleofPharmacy:Smith,
Kline&French,WyethandOthers(1959):3041.18
J.F.Marion,TheFineOldHouse:Smith,KlineCorporation'sFirst150Years
(Philadelphia:SmithKline,1980).19
R.M.Shryock,
TheDevelopmentofModernMedicine.AnInterpretationofthe
SocialandScientificFactorsInvolved(NewYork:Hafner,1969)M.Fishbein,AHistory
oftheAMA18471947(Philadelphia:W.B.Saunders,1947):3542Peter
Temin,Taking
YourMedicineDrugRegulationintheUnitedStates(Cambridge,Mass:Harvard
UniversityPress,1980):2.20
B.McNamara,(1976)D.Armstrong,E.M.Armstrong, TheGreatAmerican
MedicineShow(NewYork:PrenticeHall,1991).
43
TheOriginsofthePharmaceuticalIndustry
44
toreceivepecuniarycompensationorpatronageforsendingprescriptionsto
21 anyapothecaryshallbedisqualifiedfrombecomingamember.
AseriesoffurthergraduatesofthePhiladelphiaSchoolofPharmacygaverisetoanew
breedofpharmaceuticalmanufacturersthathadtheskillstodevelopnoveldosageformsof
ethicaldrugs.ThefirmofWilliamR.WarnerwasfoundedinPhiladelphiain1856andhis
futurepartnerinWarnerLambertwasapharmacygraduateofPhiladelphiain1884,as
weremanyotherfoundersofpharmaceuticalfirms,includingHenryWellcomein1874
andSilasBurroughsin1877.
FrederickBeldingPower,wholaterjoinedBurroughs22
Wellcomeasachemistalsotrainedthere.
ThefirmofJohnWyeth&Co.originatedfromapharmacyopenedbyFrankand
JohnWyethin1860.JohnWyethgraduatedfromthePhiladelphiaCollegeofPharmacy
withathesisonthechemicalconstituentsofvariousplantsandFrankWyeth,achemist,23
alsoattendedthecollege.
JohnWyeth&Co.prosperedbysellingproprietarymedicines 24
duringtheAmericancivilwarwithaturnoverofover$600,000.
Buttheywerealsoan
innovativefirmthatintroducednewmarketingpracticesaswellasnewdrugformulations.
Asearlyas1861theyjoinedthetwomostlikemindedfirms,H.K.MulfordandSmith&
Kline,tofoundthePhiladelphiaDrugExchange,tocampaignfortheabolitionofstamp
dutyonpatentmedicines,becausemanyoftheethicalfirmsstillsoldtheseinparallel.The
Exchangealsoestablishedasystemforchemicallytestingimporteddrugs,particularly
patentmedicines,whichenteredAmericadespitealawbanningtheimportationofpoor25
qualitymaterials.
WyethandtheircolleaguesintheDrugExchangeactivelydistinguishedthemselves
fromthemanufacturerswhomadeonlypatentmedicines,byalsoproducingpurifieddrugs
ofknowncompositionsoldonlytodoctorsandpharmacists,oftenusingesotericscientific21
JonathanLiebenau,MedicalScienceandMedicalIndustry:TheFormationofthe
AmericanPharmaceuticalIndustry,(Basingstoke:MacMillan,1987):2627.22
J.W.England(ed.),(1922):1378,200ff.,216,410.
23
J.T.Mahoney,Philadelphia:CradleofPharmacy:SmithKline&French,Wyeth
andOthers(1959):3041L.G.Blochman,(1958)JonathanLiebenau,(1987):2223.24
25
J.WyethtoBurroughsWellcome,(31October1887),WF:88/47:8.
JonathanLiebenau,(1987):23J.W.England(ed.),(1922):132.
44
TheOriginsofthePharmaceuticalIndustry
45
26 terminologysuchas'dialysed'iron.
TheymetareadymarketamongAmericandoctors
whowishedtominimisethepracticeofselfprescribingbypatients.OtherUSfirmswith
rootsinpharmacyincludedA.P.Sharp,foundedin1827inBaltimore,thefirstinAmerica27
toproducealkaloids.
CharlesErhardtandCharlesPfizerestablishedtheirfirmin28
Brooklyn,NewYorkbetween18458afterPfizerhadbeenapprenticedtoanapothecary.
HarveyC.ParkeandGeorgeS.DavisformedParkeDavisasasmallmanufacturing
businessinDetroitin1866,andW.E.UpjohnfoundedTheUpjohnPillandGranule29
CompanyinKalamazooin1886toproducefriablepills.
TheprincipaladvancesbyAmericanfirmswereincreatingnoveldosageforms
suchassugarcoatedpills,whichwereconvenienttocarry,andsugarmaskedanybitter30
tastes. Large
scalemanufactureofpillsdevelopedfrom1857,andelixirs(solubleliquid
31 forms)from1859.
Wyethpreparedcompressedhypodermictablets,andtablettriturates
werefirstmadein1861.Thesecouldbereadilydissolvedforinjectionorfortakingas32
solutions.
Thefirstmouldedmedicinesandcompressedpillsweremanufacturedin 33
Philadelphiain1863andtabletsweremadecommerciallyfrom1869.
Wyethemployees
designedandpatentedthefirstrotarytabletpressinAmericain1872toproduceopiates,
digitalis,strophanthusandquininetablets.By1876patentsweresecuredontheprocess
26 2728
J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8.
J.T.Mahoney,Merck&Co.(1959):2012.
S.Miles,Pfizer,anInformalHistory
(NewYork:Pfizer,1978)J.G.Lombardino,
ABriefHistoryofPfizerCentralResearchBull.Hist.Chem.25.1(2000):1015.29
LeonardEngel,MedicineMakersofKalamazoo (NewYork:McGraw
Hill,1961) CecilRoberts,ACenturyofCaring,Upjohn:Achievement
(Kalamazoo:Upjohn,1938).30
C.Gunn,AHistoryofSomePharmaceuticalFormulationsinF.N.L.Poynter
(ed.),(1965):13150.31
L.F.Kebler,TheTabletIndustry
itsEvolutionandPresentStatus:Compositionof
TabletsandMethodsofAnalysisJournaloftheAmericanPharmaceuticalAssociation
3 (1914):82048,937,958,106299.32
J.T.Mahoney,Philadelphia:CradleofPharmacy:SmithKline&French,Wyeth
andOthers(1959):312.33
NoteaboutBrockedon'sPatentPharmaceuticalJournal 3(1844):554T.H.
Bishop,InventoroftheCompressedTablet,WilliamBrockedonChemist&Druggist
162(28August1954):209F.N.L.Poynter,(1965):13149.
45
TheOriginsofthePharmaceuticalIndustry
46
34 andthemethodofcompressionofpills.
Incontrast,Britainspillsweremadebyhand
untilAllen&HanburysboughttheirfirstpillmakingmachineatthePharmaceutical
exhibitioninPhiladelphiain1876,buteventhennotabletswe