Table Of ContentSpringer Series in Pharmaceutical Statistics
Christy Chuang-Stein
Simon Kirby
Quantitative
Decisions
in Drug
Development
Springer Series in Pharmaceutical Statistics
Editors
F.Bretz
P.Müller
T.Permutt
J.Pinheiro
Moreinformationaboutthisseriesathttp://www.springer.com/series/15122
Christy Chuang-Stein (cid:129) Simon Kirby
Quantitative Decisions
in Drug Development
ChristyChuang-Stein SimonKirby
Kalamazoo,Michigan PfizerStatisticalResearch&ConsultingCenter
USA Cambridge,UnitedKingdom
ISSN2366-8695 ISSN2366-8709 (electronic)
SpringerSeriesinPharmaceuticalStatistics
ISBN978-3-319-46075-8 ISBN978-3-319-46076-5 (eBook)
DOI10.1007/978-3-319-46076-5
LibraryofCongressControlNumber:2017940796
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Christy Chuang-Stein
To my parents, Bruce, Terresa, and Isaac
Simon Kirby
To Dad, Mum, Katie, Theo, Helen,
Rob, and Andy
Preface
Developinganewdrugisahigh-riskandhigh-rewardenterprise.Thehighriskis
reflectedbythegenerallylowsuccessrateofturninganewmolecularentityintoan
approveddrug.Thesuccessratehasfluctuatedovertimeandhasalsovariedacross
therapeutic areas. While the success rate has improved in recent years for cancer
drugsduetotheadventoftargetedtherapies,theratehasbeendisappointinglylow
forcertaindisorderssuchasAlzheimer’sdisease.
Inadditiontothehighrisk,thecostofdevelopinganewdrughasincreasedata
pace faster than inflation. Tufts Center for the Study of Drug Development has
publishedaseriesofreportsexaminingtheaveragepretaxindustrycosttobringa
newmedicinetothemarket.Themostrecentreport,publishedin2014,estimated
anaveragecostaround2.56billionUSDin2013money.Bycomparison,in2003,
thecostwasabout1.04billionUSDin2013money,basedonthesamemethodof
calculation. While some researchers have questioned these figures, these reports
nevertheless show a substantial increase in the cost of drug development over a
decade.
The low success rate and the high cost have motivated many pharmaceutical
companiestolookforbettermethodstomakeportfoliodecisionsincludingwhether
toinvestinaparticularnewmolecularentityandhowtomakeGo/No-Godecisions.
Sincethemajorityofdevelopmentprogramsarelikelytofail,itisimportanttobe
abletoterminateaprogramwithalowprobabilityofsuccessasearlyaspossible.
Making efficient decisions requires designing efficient trials. Developing inno-
vative designs that can enable good quantitative decisions at the earliest time
possible has been the focus of much research in recent years. Many books have
beenwrittenaboutclinicaltrialdesignstosupportdrugdevelopment.Therefore,we
have decided to focus on methods for making quantitative decisions in this book.
Because of the inseparable relationship between designs and decisions, we also
spendagoodportionofthisbookdiscussingdesignoptions.
AtPfizer,thejourneytoquantitativedecisionsbeganduringthefirstdecadeof
thetwenty-firstcentury.Theimplementationbeganwithproof-of-conceptstudies.
Teamsdesigningtheseearlystudieswererequiredtopresent,toatechnicalreview
vii
viii Preface
committee,theoperatingcharacteristicsoftheirtrials/decisionruleswithrespectto
thetargetproductprofile.Themovetoassesstheprobabilityofsuccessinlate-stage
trialswasfirmlyinplacebytheyear2010withtheestablishmentofaProbabilityof
TechnicalandRegulatorySuccess(PTRS)Council.
Manystatisticiansandscientistsplayedacriticalroleintheabovejourney.The
inputfromcommercialcolleagueshelpedsolidifytheneedtoquantitativelyincor-
porate the target product profile when designing a trial and setting up the subse-
quentdecisionrule.Wehavelearnedagreatdealfromtheearlypioneeradvocates
atPfizer.Theirworkinspiredustowritethisbook.Weareparticularlyindebtedto
Mike Brown, Alan Clucas, Vlad Dragalin, Wayne Ewy, Bradley Marchant, Ken
Kowalski,MikeKSmith,JonathanFrench,CyrusHoseyni,RichardLalonde,Scott
Marshall,PeterMilligan,MohanBeltangady,PhilWoodward,JoannaBurke,Neal
Thomas,andLiamRatcliffefortheirscientificandorganizationalleadership.
The book has 13 chapters. Chapter 1 offers a high-level overview of clinical
testing and regulatory review of a pharmaceutical product. Chapter 2 reviews the
Frequentist approach to the testing of hypotheses and in particular the two-action
decisionproblem.Inthecontextofdrugdevelopment,thetwoactionscorrespond
to progressing or not progressing a drug for further development. Chapter 3 dis-
cussesthemetricscommonlyusedtocharacterizetheperformanceofadiagnostic
test. Chapter 4 draws an analogy between successive trials conducted during the
clinicaltestingofaninvestigationalproductandaseriesofdiagnostictests.Under
this analogy, the condition to diagnose by a clinical trial is the existence of a
clinically meaningful effect of the investigational product. We have found this
analogyparticularlyusefultoexplaintoournonclinicalcolleagueswhyreplication
is such an important concept indrug development and to show why replication is
notaseasyasmanypeoplemighthope.
The predictive power of a diagnostic test depends on the existing information
concerningtheprevalenceoftheconditiontobediagnosedinarelevantpopulation.
Similarly, the predictive power of a clinical trial depends on available prior
knowledge concerning the investigational product. Articulating such prior knowl-
edge is the topic of Chap. 5. In Chap. 6, we describe metrics that are useful to
evaluate designs and associated decision rules for efficacy assessment at various
stagesofpremarketingdevelopment.Thefocusonefficacyisduetothegenerally
well-defined endpoints to decide the beneficial effect of a new drug. Chapter 7
covers the proof-of-concept stage, while Chaps. 8 and 9 cover the dose-response
andconfirmatorystage,respectively.
Chapter10focusesonassessingthedesignofatrialforcomparativeeffective-
nessassessment.Bycomparativeeffectiveness,wemeanthecomparisonofdiffer-
entactivetreatmentstodeterminewhich treatmentworksbest.Thisfocusreflects
theincreasingimportanceofthesecomparisonsinthemarketplaceduetotheneed
tojustifythepriceandtoqualifyforreimbursement.
The metrics used in Chaps. 7–10 do not include any cost consideration explic-
itly. But, cost is an integral part of drug development strategy optimization.
Incorporating cost into design consideration is the topic of Chap. 11 with two
example approaches. The first one optimizes a benefit-cost efficiency score that
Preface ix
measures the cost-effectiveness of a proof-of-concept trial design. The second
approachcombinescostsandpotentialcommercialreturnstoassessdrugdevelop-
ment options. The chapter includes a detailed discussion on the calculation of the
expected net present value which could be of interest to readers without much
exposuretoproductvaluation.
In Chap. 12, we examine the bias that can be produced by the use of Phase 2
resultsthathavebeenselectedbecauseofafavorableoutcome.Wehavehintedat
thissourceofbiasinearlierchaptersandhavededicatedChap.12tothisissue.We
offer recommendations on how to correct for this bias when using prior positive
resultstodesignthenexttrial.
Inthefinalchapterofthebook,weincludeselectedtopicsthataffectdesignand
decision choices at all stages of drug development. Examples include adaptive
designs,benefit-risk,andeconomicassessment.Theseareallactiveresearchareas.
Even though we offer some references, it is not our intent to cover these areas in
detailinthisbook.
The book is written for readers with a broad range of responsibilities in drug
development. While the book contains a lot of technical details for quantitative
scientists, it also contains plenty of concepts presented in a unified framework
which, we believe, can help less quantitative readers make more quantitative
decisions.
Wehopeyouwillenjoyreadingthebookasmuchaswedidwritingit.
Kalamazoo, MI, USA ChristyChuang-Stein
Cambridge,UK SimonKirby
May2017
Contents
1 ClinicalTestingofaNewDrug. . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 ClinicalDevelopment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.1 Phase1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.2 Phase2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.2.3 Phase3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.2.4 Phase4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.3 RegulatoryReview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.3.1 AcceleratedApproval. . . . . . . . . . . . . . . . . . . . . . . 9
1.3.2 BreakthroughTherapy. . . . . . . . . . . . . . . . . . . . . . . 10
1.3.3 PriorityReview. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.3.4 FastTrack. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.3.5 OrphanDrug. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.3.6 DrugApprovalintheEuropeanUnion(EU). . . . . . . 12
1.4 InnovativeDesigns. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.4.1 AdaptiveDesign. . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.4.2 MasterProtocol. . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.5 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2 AFrequentistDecision-MakingFramework. . . . . . . . . . . . . . . . . 19
2.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.2 StatisticalHypotheses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.3 TestingaStatisticalHypothesis. . . . . . . . . . . . . . . . . . . . . . . 20
2.4 Decision-Making. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.5 LossesandRisks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.6 ThePowerFunctionofaTest. . . . . . . . . . . . . . . . . . . . . . . . 24
2.7 DeterminingaSampleSizeforanExperiment. . . . . . . . . . . . 25
2.8 MultistageTestsandtheUseofaNo-DecisionRegion. . . . . . 28
2.9 One-SidedVersusTwo-SidedTests. . . . . . . . . . . . . . . . . . . . 28
xi
