Antibiotics: The Perfect Storm

110 Pages·2010·1.57 MB·English

by  David M. Shlaes (auth.)

Antibiotics

David M. Shlaes
Antibiotics
The Perfect Storm
1 3
DavidM.Shlaes
Anti-infectivesConsulting,LLC
MontaukAvenue219
06378Stonington
CT,USA
[email protected]
ISBN978-90-481-9056-0 e-ISBN978-90-481-9057-7
DOI10.1007/978-90-481-9057-7
SpringerDordrechtHeidelbergLondonNewYork
LibraryofCongressControlNumber:2010934450
©SpringerScience+BusinessMediaB.V.2010
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ToJanforyearsofhardwork,patience,
understanding,loveandsupport.
David M. Shlaes MD, PhD has had a 30-year career in anti-infectives spanning
academiaandindustrywithalong-standingscientificinterestinantimicrobialresis-
tance. In 1991 he was appointed Professor of Medicine at Case Western Reserve
University. In 1996, Dr. Shlaes became vice president for Infectious Diseases at
Wyeth Research for 6 years, assuming responsibility for the strategic direction
for infectious diseases within Wyeth. In 1998 Dr. Shlaes was the cover feature
in the April issue of Business Week dedicated to antibiotics research. In 2002,
Dr.Shlaesbecameexecutivevicepresident,ResearchandDevelopmentforIdenix,
Pharmaceuticals,acompanylocatedinCambridge,MA,focusedonthediscovery
anddevelopmentofantivirals.In2005,heleftIdenixtoformaconsultingcompany
forthePharmaceuticalIndustry(Anti-InfectivesConsulting,LLC).Hewasrecently
anindependentdirectorforNovexel,S.A,ananti-infectivesbiotechinParisthatwas
justsoldtoAstra-Zeneca.Heconsultsforanumberofotheranti-infectivefocused
biotechs and frequently works with VC firms in the evaluation of anti-infective
companies.
Contents
1 ThePerfectStorm . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 TheMiracle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3 Resistance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
TheBasics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
AntibioticsforAnimalsandCropsLeadtoResistanceforPeople . . . . 16
InOurHospitals,ThingsAreGettingCritical . . . . . . . . . . . . . . 20
AntibioticResistancePlusToxinProductionEqualsDeath . . . . . . . 23
OurCommunitiesareNotSpared . . . . . . . . . . . . . . . . . . . . . 25
Resistance–SummingUp . . . . . . . . . . . . . . . . . . . . . . . . 27
4 TheFDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
WeNeedThem,butTheyHaveBecomePartoftheProblem . . . . . . 29
TheFDAIncreasesClinicalTrialDesignStringencyandCosts.
CompaniesAbandonAntibioticResearch . . . . . . . . . . . . . . . . 32
“Mild”InfectionsRequirePlacebo-ControlledTrials–Industry
Balks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
NewAntibioticsforMildInfectionsAreForcedfromtheMarket
WhileGenericAntibioticsAreStillApprovedintheAbsence
ofPlacebo-ControlledTrials . . . . . . . . . . . . . . . . . . . . . . . 38
TheKetekScandal . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Pneumonia–TheNewFrontier.NewTrialRequirementsfor
Pneumonia Will Make Approval Much More Difficult and
CostlyandSometimesSimplyInfeasible . . . . . . . . . . . . . . . . . 41
The FDA Can Change Its Requirements After Completion
ofaTrialandthenRequireNewTrialsforApproval . . . . . . . . . . . 44
TheFDAisRegulatingItselfOutoftheAntibioticsBusiness . . . . . . 46
WeNeedBalanceandPerspectivefromtheFDA . . . . . . . . . . . . 47
TheFDAMakesItDifficultforThemtoObtainGoodAdvice . . . . . 48
5 Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
6 TheIndustry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
AntibioticsFormaCornerstoneofthePharmaceuticalIndustry . . . . . 57
ResistanceShouldCreateOpportunities . . . . . . . . . . . . . . . . . 60
vii
viii Contents
IndustryConsolidationReducestheEffortinAntibiotics . . . . . . . . 61
AntibioticsAreNotFinanciallyAttractiveintheConsolidated
Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
IndustryTakesaRisk-AverseApproachtoItsClinicalTrials,
butDeprivesUsoftheMostImportantInformation . . . . . . . . . . . 65
DiscoveryofNewAntibioticsIsBecomingHarder . . . . . . . . . . . 66
TheUSMarketShareisStagnantorShrinking.WilltheIndustry
beAbletoPrioritizeEx-USTerritories? . . . . . . . . . . . . . . . . . 67
ResearchandDevelopmentCostsIncrease,butApprovalsAreDown . . 68
SomeGoodNewsforEveryone. . . . . . . . . . . . . . . . . . . . . . 69
AntibioticR&DinBiotechIsStymiedbyLateStageClinical
TrialCosts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
BiotechIsStillaHigh-RiskProposition . . . . . . . . . . . . . . . . . 73
7 ModestProposals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
TheRoleofGovernment . . . . . . . . . . . . . . . . . . . . . . . . . 77
GovernmentLovesaTaskForce . . . . . . . . . . . . . . . . . . . . . 77
GovernmentCanPlaySeveralImportantRoles . . . . . . . . . . . . . 79
TheTransatlanticTaskforceonAntimicrobialResistance . . . . . . . . 81
Government-SponsoredResearchandResearchToolsAreRequired . . 81
IndustryIncentivesWillProbablyAlsoBeRequired.Europe
IsLeadingtheWayinThinkingHere . . . . . . . . . . . . . . . . . . . 82
TheFDA(andEMEA) . . . . . . . . . . . . . . . . . . . . . . . . . . 84
TheFDAandEMEABothMustAdaptaMoreBalanced
ApproachtoAntibiotics.RequiredTrialDesignsMustBeFeasible. . 84
DoWeWantNewAntibioticsforMildInfections?IsBacterial
BronchitisintheSettingofChronicLungDiseaseaMild
Infection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
TheFDAMustModifyItsGuidelinesforClinicalTrials
inCommunityAcquiredBacterialPneumonia . . . . . . . . . . . . . 85
TheFDAHastoStopMovingtheGoalPostsinMid-Stream . . . . . . 87
TheFDAHastoLevelthePlayingFieldwithGenericAntibiotics . . . 88
CongressNeedstoStepBackfromtheFDAEspeciallyWhere
ScienceIsConcerned . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
OurGovernmentNeedsAccesstotheBestAdviceitCanGet . . . . . . 89
HowAboutaTotallyNewApproachtoDrugDevelopment? . . . . . . 89
Communication Between the Industry and Physicians
IsRequired,butisBecomingMoreandMoreRestricted . . . . . . . . 91
WhatShouldtheIndustryBeDoing? . . . . . . . . . . . . . . . . . . . 92
TheCurrentLargePhRMAModelIsnotViable.TheseGiants
NeedtoDivideThemselvesintoBite-SizePortionstoSurvive . . . . . 93
8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Chapter 1
The Perfect Storm
On the antibiotics front, the weather has occasionally been bad ever since I can
remember.Butthingshaveneverbeenasbadastheyaretoday.Bacteriaarebecom-
ingresistanttothepointwherenoneofouravailableantibioticsworkforsomeof
theinfectionsthatconfrontpatientsandphysiciansinhospitalsaroundtheUSand
thearoundworld.Forthesepatientsweareslippingbackintimetoapre-antibiotic
erawherewehavelittletoofferbutcomfortfordiseaseswhichwehavebeeneasily
abletocureoverthelast50years.
But in answer to resistance, our antibiotic pipeline is all but dry and the sit-
uation is deteriorating. The science of discovering new antibiotics is exceedingly
challengingandtheeconomicsofantibioticsarebecominglessandlessfavorable.
TheregulatoryagenciesliketheFDAarecontributingtotheproblemwithaconstant
barrage of clinical trial requirements that make it harder, slower and more costly
to develop antibiotics. The pharmaceutical industry, under extraordinary financial
pressures, is consolidating at historic rates leaving fewer and fewer large compa-
niesstanding.Theantibioticmarketisnotaspromisingasmarketsfortreatmentof
chronicdiseaseslikehighcholesterolorchronicdepressionorhighbloodpressure.
Forthosediseaseswhichwecannotcure,thedrugsmustbetakenforlongperiods
oftime,frequentlyforalifetime.Antibiotics,whichactuallycuredisease,areonly
takenfordaysorweeks.
In response to all these pressures, of the large pharmaceutical companies still
extant,fewerandfewerareremainingactiveinantibioticresearch.Ifthisisn’tThe
PerfectStorm,Idon’tknowwhatis.
There are possible solutions to this conundrum. They include incentives to
companiesforantibioticresearchanddevelopment,deconsolidationwithinthephar-
maceutical industry and affecting a more balanced approach within the FDA that
assuresustheabilitytodevelopnewantibioticsforresistantbacteria.
Basically,weeitherinvestnowwithorganization,balanceandmoneyorwewill
paywithourlives.Antibioticsaregoingthewayofthedodobutbacterialpathogens
arewithusfortheduration.
IfeellikeI’vebeenfightingthisbattleallmylife.WhenIfinishedtrainingand
started my career in academic medicine, I wanted to study antibiotic resistance in
bacteria.Ifeltthatifweunderstoodhowresistancespread,wecouldstopit.Ifwe
D.M.Shlaes,Antibiotics,DOI10.1007/978-90-481-9057-7_1, 1
(cid:2)C SpringerScience+BusinessMediaB.V.2010