Appropriate Dose Selection — How to Optimize Clinical Drug Development

223 Pages·2007·1.7 MB·English

by  T. Singer (auth.)

Ernst Schering Research Foundation Workshop 59
Appropriate Dose Selection –
How to Optimize Clinical Drug Development
Ernst Schering Research Foundation
Workshop 59
Appropriate Dose Selection –
How to Optimize Clinical
Drug Development
J. Venitz, W. Sittner
Editors
With 36 Figures
123
SeriesEditors:G.StockandM.Lessl
LibraryofCongressControlNumber:2006928310
ISSN 0947-6075
ISBN-10 3-540-27867-2 SpringerBerlinHeidelbergNewYork
ISBN-13 978-3-540-27867-2 SpringerBerlinHeidelbergNewYork
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Preface
Cancerhasbecomeachronicdisease,oftenrequiringlong-term,chronic
oncologicaldrugtreatment.Asaresult,theoncologicaltreatmentisex-
posedtoalargenumberofpatientswhomaybeonconcurrenttreatments
for other health conditions and/or who may suffer from concomitant
illnesses,bothofwhichmayaffecttheefficacyandsafetyoftheonco-
logicaltreatmentbycontributingtotheincreasedincidenceofadverse
eventsand/orlossofefficacy.
VI Preface
Newer oncological drugs also have become more targeted to the
underlyingdiseaseprocess(es),andtheiruseanddosageregimensmay
needtobetailoredtoindividualpatients. Therefore,asopposedtothe
olderchemotherapeuticdrugs,thesenewagentsareusuallynotdosedto
theirmaximaltolerateddose(MTD),andoptimaldoseindividualization
hasbecomemoreimportanttoimprovetheirclinicalefficacyandsafety.
Atthesametime,theoveralldrugdevelopmentprocesshasbecome
more time-consuming and expensive while more potential biological
targetsincancerarebeingexplored.Noveldrugcandidatesarescreened
inearlyclinicaldrugdevelopment(ECDD),basedontheirclinicalsafety,
pharmacokinetic(PK)propertiesandachievementofdesiredbiological
effects;drugcandidatessurvivingthisearlyclinicalscreenundergomore
rigorousandlarge-scalephaseIIItestingtodemonstratetheirsafetyand
efficacyforregulatoryapprovalandclinicaluse.
Unfortunately, quite a few of these new oncological agents, both
approvedandunderdevelopment,havelessfavorablebiopharmaceuti-
calcharacteristics,especiallyforchronicoraladministration,e.g.,poor
gastrointestinal solubility and/or permeability and/or extensive drug
metabolism, leading to low oral bioavailability and a high degree of
variabilityamongpatientsinsystemicdrugexposureandpharmacody-
namic(PD)orclinicaldrugresponse.Effectivechroniccancertreatment
requiresinformationonintrinsicandextrinsicpatientfactorsimpacting
the clinical drug response, e.g., drug–drug interactions (DDIs), phar-
macogenetic (PG) differences, etc. The basic sciences provide more,
albeit incomplete, knowledge about the fundamental mechanisms of
drug disposition, such as drug transporters and metabolic pathways
as well as disease biology, such as biological targets, pathophysio-
logical pathways, and intermediate markers, i.e., potential biomarkers
(BMs).
Thisincreasingbodyofknowledgeisonlyslowlytranslatedintothe
optimalclinicaluseoftheseagents:
• We appreciate the role that patient subpopulations may play in the
outcomesofclinicaltrials,basedontheirresponseorlackthereofto
drugtreatment.
• WearelearningmoreaboutpossibleBMsofdrugresponse,efficacy,
andsafety,whichmayassistinoptimaldosefinding.
Preface VII
• Wemayhavetocarefullyindividualizedosageregimensforindivid-
ualpatients.
Optimal dose finding requires integration of exposure–response (ER)
relationshipsthroughouttheclinicaldrugdevelopment(CDD)process
byquantitativemethods.FrontloadingCDDtofailpoordrugcandidates
early in the development process has put the burden on early clinical
drugdevelopmentto:
• Provideearlyproofof(biologicaland/ortherapeutic)concept(POC)
fornoveltargets/drugcandidatesinordertomakego/nogodecisions.
• Rationally select dosing regimens in phase I and II information to
optimize chances ofsuccess in phaseIIIby integrating information
across in vitro/in vivo (different species) PK/PD/clinical studies to
selectappropriatedosesandBM.
• Supportdrugproductlabelinginformationforsafeandeffectiveuse
inpostapprovalclinicaluse.
Ultimately,theclinicaldevelopmentprocesshastoprovidethefollowing
information for the optimal clinical use in order to minimize risk and
maximizebenefitofthenewdrugtreatment:
1. Whataretheoddsofachievingdesiredclinicaloutcomes,i.e.,efficacy
withouttoxicity?
Whichpatientsareathighorlowriskorstandtobenefitthemost?Can
these subpopulations be identified a priori? How should the dosage
regimenbeindividualizedtominimizeharmandmaximizebenefit?
What marker or level of exposure can be monitored during long-
term treatment, and how should the dosage regimen be adjusted, if
necessary,e.g.,duetoDDI?
2. Whatarethestakesintermsofbenefitorharm?
What are the clinical consequences of lack of efficacy and adverse
events,giventheseriousnessoftheunderlyingcancerdisease?What
areclinicalalternativedosingregimens,drugcombinations,orother
treatments?
The answers to these questions, based on empiric evidence, theoret-
ical considerations (e.g., PK/PD modeling), and clinical judgment are
VIII Preface
mandatoryprerequisitesforrationaldrugdevelopmentandriskmanage-
mentbydrugdevelopersandmanufacturers,regulatoryagencies,health
careproviders,andsocietyatlarge.
This workshop brought together experts from throughout the world
topresentanddiscussthefollowingissues:
1. HowtodemonstratePOC(biological/therapeutic)inECDDandhow
todesignpivotalphaseI/IIprograms.
2. HowtoevaluateBMinECCDandthroughoutCDD.
3. HowtoexploreERfordrugresponseandtoxicitythroughoutCDD
andhowtodesignoptimaldoserangingstudiesinphasesIandII.
4. How to select an appropriate, i.e., likely to succeed in phase III,
dosingregimeninECDDandhowtodefine“optimaldose”.
5. Howtolabel adrugproductforsafeandeffectiveclinical useafter
approvalinthemarketplace.
Afterexcellentpresentationsandfrankdiscussions,consensusemerged
that the current preponderance of empiricism in oncology drug devel-
opmentshouldbereplacedbyabettermechanisticunderstandingofthe
underlyingdiseasebiologyandtargetalongwiththehumandrugdispo-
sitionfortheneweragents,especiallythetargeteddrugs.Co-developing
BMwiththedrugcandidateearlycanbeextremelyhelpfulinearlyPOC
and better doseselection. This mayalso help tofailearly andcheaply
drugcandidateswithalowlikelihoodtosucceedinphaseIII.Inaddition,
betterdose–responsetrials(e.g.,randomizedphaseIItrials)areneeded,
incorporatingBMand/orclinicalresponse;however,theconceptofthe
optimalbiologicallyeffectivedosehasbeenquestionedrecentlydueto
our knowledge gap in disease biology. Given the increasing polyphar-
macy and co-morbidities in cancer patients, it has become essential to
identifyimportantclinicalcovariates,leadingtoPKandPDvariability
amongpatients.Finally,optimaldosefindingduringdrugdevelopment
is not only able to streamline the drug development and improve drug
productlabeling,butalsohelpsavoidpostmarketingchangesinlabeling
orevenmarketwithdrawals.
WeexpressourgratitudetotheErnstScheringResearchFoundation
(ESRF)andDr.MonikaLesslfortheirfinancialandlogisticsupportof
this workshop. We also wish to acknowledge the contributions of Dr.
BerndMüller,HeadofGlobalPreclinicalDevelopment,ScheringAG,as
Preface IX
wellFrauYvonneSpiegel,ScheringAG,andFrauKarolaSzivos,ESRF
in organizing theevent. We gratefully recognize theinvited presenters
and moderators for their lectures, manuscripts, and discussion leads.
Finally, we wish to thank the workshop audience for their insightful
questionsandcommentsthatmadethisworkshopasuccess.
WolfSittner
JürgenVenitz
Contents
1 ExtrapolationofPreclinicalDataintoClinicalReality–
TranslationalScience
T.Singer . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 SmarterCandidateSelection–
UtilizingMicrodosinginExploratoryClinicalStudies
P.Buchan . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3 TheApplicationsofBiomarkers
inEarlyClinicalDrugDevelopment
toImproveDecision-MakingProcesses
J.Kuhlmann . . . . . . . . . . . . . . . . . . . . . . . . . 29
4 UsingExposure–ResponseandBiomarkers
toStreamlineEarlyDrugDevelopment
J.Venitz . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5 ExperienceswithDoseFindinginPatients
inEarlyDrugDevelopment:
TheUseofBiomarkersinEarlyDecisionMaking
S.R.Sultana,S.Marshall,J.Davis,B.H.Littman . . . . . . 65
6 GenotypeandPhenotypeRelationshipinDrugMetabolism
I.Roots,G.Laschinski,F.Arjomand-Nahad,J.Kirchheiner,
D.Schwarz,J.Brockmöller,I.Cascorbi,T.Gerloff . . . . . 81
XII Contents
7 ClinicalTrialsinElderlyPatients
S.H.D.Jackson . . . . . . . . . . . . . . . . . . . . . . . . 101
8 DoseFindinginPediatricPatients
G.Henze . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
9 IntegrationofPediatricAspects
intotheGeneralDrugDevelopmentProcess
K.Rose . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
10 CurrentStumblingBlocksinOncologyDrugDevelopment
C.D.Gimmi . . . . . . . . . . . . . . . . . . . . . . . . . 135
11 ExploratoryIND:ANewRegulatoryStrategy
forEarlyClinicalDrugDevelopmentintheUnitedStates
N.Sarapa . . . . . . . . . . . . . . . . . . . . . . . . . . 151
12 EthnicAspectsofCancerTrialsinAsia
T.W.T.Leung . . . . . . . . . . . . . . . . . . . . . . . . . 165
13 EvaluationoftheEffectonCardiacRepolarization
(QTcInterval)ofOncologicDrugs
J.Morganroth . . . . . . . . . . . . . . . . . . . . . . . . 171
14 TheRoleofPETScanning
inDeterminingPharmacoselectiveDoses
inOncologyDrugDevelopment
P.Price . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
15 BiometricalAspectsofDrugDevelopment
D.Machin,S-B.Tan . . . . . . . . . . . . . . . . . . . . . 195
16 PreventingPostmarketingChangesinRecommendedDoses
andMarketingWithdrawals
C.Peck . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
PreviousVolumesPublishedinThisSeries . . . . . . . . . . . . 217