Table Of Contentfm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount=
Critical Pathways
to Success in CNS
Drug Development
Critical Pathways to Success in CNS Drug Development
Neal R. Cutler, John J. Sramek, Michael F. Murphy, Henry Riordan, Peter Bieck and Angelico Carta
© 2010 NR Cutler, JJ Sramek, MF Murphy, H Riordan, P Bieck and A Carta. ISBN: 978-1-444-33064-9
i
fm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount=
Critical Pathways
to Success in
CNS Drug
Development
Neal R. Cutler,
M.D.
PresidentandCEO,WorldwideClinicalTrials
BeverlyHills,CA,USA
John J. Sramek,
Pharm. D.
DirectorofClinicalResearch,WorldwideClinicalTrials
BeverlyHills,CA,USA
Michael F. Murphy,
M.D., Ph.D.
ChiefMedicalandScientificOfficer,WorldwideClinicalTrials
KingofPrussia,PA,USA
Henry Riordan,
Ph.D.
Sr.VPMedicalandScientificAffairs,WorldwideClinicalTrials
KingofPrussia,PA,USA
Peter Bieck,
M.D., Ph.D.
VicePresidentofClinicalResearch,WorldwideClinicalTrials
Indianapolis,IN,USA
Angelico Carta,
M.D.
President,WorldwideClinicalTrialsEurope
London,UK
A John Wiley & Sons, Ltd., Publication
iii
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Thiseditionfirstpublished2010,(cid:1)c 2010byNRCutler,JJSramek,MFMurphy,HRiordan,PBieck
andACarta
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LibraryofCongressCataloging-in-PublicationData
CriticalpathwaystosuccessinCNSdrugdevelopment/NealR.Cutler...[etal.].
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN978-1-4443-3064-9
1.Neuropsychopharmacology. 2.Drugdevelopment. 3.Criticalpathanalysis. 4.Central
nervoussystem–Effectofdrugson–Research–Methodology. I.Cutler,NealR.
[DNLM:1.CentralNervousSystemAgents–pharmacology. 2.ClinicalTrialsasTopic–methods.
3.DrugEvaluation–methods. 4.DrugEvaluation,Preclinical–methods.QV76.5C9342010]
RM315.C7152010
615(cid:1).78–dc22
2009035146
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
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PrintedinSingapore
1 2010
iv
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Contents
Acknowledgments,vi
Foreword,vii
1 TheimpendingcrisisinCNSdrugdevelopment,1
2 AnimalmodelsandproceduresforCNSdisorders,14
3 Preclinicalantecedentstoearlyhumanclinicaltrials,70
4 Biomarkersandsurrogatemarkersindrugdevelopment,101
5 Neuroimagingandcognitiveassessmentsinearlydrug
development,167
6 BridgingandCSFstudies,187
7 Acasestudyfrompreclinicaltoearlyclinicaltrials,230
Index,254
v
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Acknowledgments
TheauthorsaregratefultoAndrewKuhlmanforhisinvaluableassistancein
helpingthemresearchtheliterature,formattables,andwritethepresentbook.
Hewasevervigilantinorganizinglargesectionsofthetext,keepingtrackof
countless references, and integrating comments from all the authors with a
unifiedwritingstyle.
We also wish to thank Tricia Long for her assistance with Chapter 6, and
William Nowatzke, Ph.D., for his contribution on laboratory biomarkers in
Chapter4.
vi
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Foreword
The process of drug development has never been as complex and costly as
ithasbecomeinthetwenty-firstcentury.Encouragedbysensationalisticand
inaccuratereportinginthelaypress,manycitizensareconvincedoftheunre-
alisticfantasythatprescriptionpharmaceuticalproductsshouldberisk-free.
Wheneffectivemedicationscauseadversereactions—astheyinevitablydo—
theresponsefromthepublicandfrompoliticiansisoutrage,withaccusations
of greed and malfeasance on the part of the pharmaceutical manufacturers
andincompetenceonthepartofregulatoryagencies.Theoutcomehasbeen
a development process driven by avoidance of liability and blame, with an
increasingmazeofpaperworkandregulationthatworkagainsttrueinnova-
tion.
Fordevelopersofnewdrugsintheareaofneuropsychopharmacology,the
alreadydifficultprocessisfurthercomplicatedbyfeaturesintrinsictothedis-
cipline. Mood, affect, thought, behavior, and cognition are not easily mea-
sured.Outcomeinstrumentsare“soft,”andresponsespotentiallymodulated
byresearchsetting,experience,expectations,andpractice.Experimentalani-
malmodelsandsurrogatemarkersofdiseaseandtreatmentarelesswellde-
velopedthaninotherdisciplines.Placeboresponseratesintrialsofneuropsy-
chiatric agents are uncomfortably high, leading to many “failed” studies in
whichevenanestablishedactivecomparatordoesnotseparatefromplacebo.
I have known Dr. Neal Cutler and his work for more than three decades.
His career represents a remarkable blend of academic achievement and en-
trepreneurialsuccess.Aphysicianandboard-certifiedpsychiatrist,Dr.Cutler
spenthisearlyprofessionalcareerasanacademicpsychiatrist,bothattheUni-
versityofCaliforniaandattheNationalInstitutesofHealth.In1987hestarted
asuccessfulclinicaltrialsite,andsubsequentlyacontractresearchorganiza-
tion(CRO)inBeverlyHills,specializinginclinicaltrialsofmarketedandcan-
didatedrugsinpsychiatryandneurology.HisworkintheCROindustryhas
broughthimtohispresentpositionasPresidentandChiefExecutiveOfficer
ofWorldwideClinicalTrialsinBeverlyHills.
TheaccomplishmentsofDr.Cutlerandhisassociatesdemonstratethatafi-
nanciallysuccessfulCROcannotonlyservethedrugdevelopmentobjectives
ofthepharmaceuticalindustry,butalsoadvancebasicandclinicalknowledge
inneuropsychopharmacology.Overtheyearstheirworkhasresultedinhun-
dreds of publications in the peer-reviewed medical and scientific literature.
Thevastexperienceofthegrouprangesfromstrategicscientificandconcep-
tualaspectsofdrugdevelopmentinpsychopharmacologytopracticalissues
vii
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viii Foreword
ofprotocoldesignandexecution,avoidanceoftypicalproblemsandpitfalls,
andcompliancewithregulatoryrequirements.
This book collates and summarizes the experiences of Dr. Cutler and his
professionalcolleagues.Itisnotananthologyofchaptersfromdifferentau-
thors at different institutions—each chapter is written by Dr. Cutler and his
collaboratingscientistsatWorldwideClinicalTrials,Inc.Itistheirexperience,
expertise,andachievementthatarerepresentedontheprintedpage.Forthose
determinedenoughtofacethehazardouslandscapeofdrugdevelopmentin
neuropsychopharmacology,thisbookwillhelp.
DavidJ.Greenblatt,MD
Boston,MA
c01 BLBK249-Cutler Trim:6inX9in December29,2009 20:14 CharCount=
CHAPTER 1
The impending crisis in CNS drug
development
Introduction
Aplethoraofinformationhasbeengatheredacrossthefieldsofneuroimag-
ing, genetics/genomics, proteomics, neurobiology, and epidemiology that
have greatly enhanced our basic knowledge of the pathophysiological and
genetic underpinnings of many common central nervous system (CNS) dis-
orderssuchasschizophrenia,Alzheimer’sdisease(AD),Parkinson’sdisease,
depression, and anxiety disorders. In fact, most of what is currently known
abouttheseCNSdisordershasbeendiscoveredinthepastdecade.However,
thesebreakthroughsintheCNSbasicscienceshavetoooftenfailedtotrans-
late into more effective, more affordable, and safer pharmaceutical products
forpatientssufferingfromthesedisorders.Muchoftheinformationresulting
fromtheseinnovationshashadlittleclinicalrelevance,anddespitethenewly
acquiredknowledgegainedthroughoutthepastfewyears,CNSdrugdevel-
opmenthasbeencharacterizedbyrelativestagnation.Infact,thenumberof
approvalsforCNSdrugsoverthepastseveralyearshasactuallydeclined!
Given the current economic climate in the US and around the world, this
situation appears to be only getting worse—there are reduced resources
available for drug development and reduced capital to fund this develop-
ment. In addition, the drug development pathway is typically cumbersome
and expensive, requiring fresh ideas and streamlined procedures to make
developmentprogramsrunfasterandcheaper,aswellasupdatedregulations
fromtheFoodandDrugAdministration(FDA)tosimplifythedrugapproval
process.Manyoftheseinnovationsalreadyexist,andarebeginningtobein-
tegratedintothedrugdevelopmentpipeline.Othersarebeingvalidatedand
maysoonbecomevitalcomponentsofthispathway.Thepharmaceuticaland
biotechnologyindustriesareonthecuspofamajorrevolutionintechnology,
procedures,andregulationsregardingdrugdevelopment—notbecausethey
wish to improve upon an already successful system, but because they need
toreplaceaflawedandbrokensystemiftheywishtoberelevantincoming
decades,andcreatenew,effectivetreatmentsforthepatientswhoneedthem
themost.
Critical Pathways to Success in CNS Drug Development
Neal R. Cutler, John J. Sramek, Michael F. Murphy, Henry Riordan, Peter Bieck and Angelico Carta
© 2010 NR Cutler, JJ Sramek, MF Murphy, H Riordan, P Bieck and A Carta. ISBN: 978-1-444-33064-9
1
c01 BLBK249-Cutler Trim:6inX9in December29,2009 20:14 CharCount=
2 Chapter1
It is with this idea in mind that we have decided to write this book. We
have compiled the latest advances in early CNS drug development from a
vast body of literature, from clinical studies, and from our own experience.
Wehaveexplainedtheseadvancesinsequential,clearlyorganizedchapters,
beginningwithpreclinicalmodelsandgoingthroughfirst-in-manclinicaltri-
als.Wehaveprovidedconcise,relevantsummariesandreviewsofthenewest
techniques, markers, and models being used and introduced into the CNS
drug development pipeline, and determined how they can be best utilized
andwhatfurthervalidationisrequired.WehavealsoreviewedthelatestFDA
regulationsandguidelines,anddiscussedhoweachoftheseaffectsthedrug
developmentindustryforbetterorforworse.
However, before we discuss the many innovations and regulations de-
signedtoaddresstheproblemsthedrugdevelopmentindustryfaces,wewish
to briefly explain the problems themselves; this way you will have a better
understandingofwhatrequiresfixing,whyitneedstobefixed,andjusthow
serioustheproblemsreallyare.
Stagnation in CNS drug development
The current stagnation in CNS drug development is evidenced by the lack
ofnoveltreatmentsacrossanumberofneurologicandpsychiatricdisorders,
withtwoofthemostrepresentativeindicationsfromthetherapeuticareaof
CNS(ADandschizophrenia)servingascompellingillustrationsofthisstag-
nation.Forexample,thelackofapprovabletherapiesthatwouldhopetomod-
ifydiseaseprogressionofADhasbeentrulyfrustrating—notonlyforphysi-
ciansandfamilymemberswhoarecaregiversforpatientswithAD,butalso
forsocietyasawhole,giventheloomingfinancialandhealthcarecrisisassoci-
atedwiththeever-increasingprevalenceofthedisease.Todate,allthedrugs
approvedtotreatAD,includingtheN-methyl-d-asparticacid(NMDA)antag-
(cid:1)
onistNamendaR (memantine),aswellasallofthecholinesteraseinhibitors,
(cid:1) (cid:1)
including RazadyneR (galantamine/previously known as ReminylR),
(cid:1) (cid:1)
ExelonR (rivastigmine), and AriceptR (donepezil), are prescribed for the
treatmentofthesymptomsofADandcarrythelabelthatthereis“noevidence
thatanyofthesedrugsalterthecourseoftheunderlyingdementingprocess.”
As an example, despite an explosion of publications advancing our un-
derstanding of the diagnostics, pathophysiology, genetics, and imaging
associated with AD, there have not been any drugs that have successfully
been shown to act as “disease modifiers.” This is certainly not for a lack
of effort: In early 2007, there were approximately 12 drugs in US phase III
clinical trials for AD, all of which showed great promise to slow or stop the
progressionofthediseasebasedontheirmechanismsofaction.Additionally,
the European Medicines Agency (EMEA) reported consulting on at least
15 different AD drugs, with 79% of their advice stemming from queries
surroundingdiseasemodification(20%wereonsymptomatictreatmentand
c01 BLBK249-Cutler Trim:6inX9in December29,2009 20:14 CharCount=
TheimpendingcrisisinCNSdrugdevelopment 3
1%wereondiagnostics)[1].Despitesomeearlysignalstothecontrary,there
(cid:1)
arenodevelopmentprogramstodate(includingNeurochem’sAlzhemedR,
Myriad Genetics’ FlurizanTM, and Wyeth/Elan’s bapineuzumab) that have
unequivocallyshownpositivetrialresults,althoughsomeinterestingtrends
werenotedthatwillbediscussedbelow.
The lack of disease modifiers is especially dire when considering that the
Alzheimer’sAssociationreportfromMarchof2007concludedthattherewere
over 5 million people in the United States living with AD [2]. This number
includes4.9millionpeopleovertheageof65andbetween200,000and500,000
peopleundertheageof65withearly-onsetADandotherdementias.Equally
alarmingaretheprojectionsforthefuture.TheprevalenceofADispredicted
to increase 27% by 2020, an astonishing 70% by 2030, and nearly 300%, to
approximately 13.2 million people, by 2050—unless a way can be found to
slowtheprogressionofthediseaseorpreventit[3].Remarkably,ithasbeen
suggested that even a “5-year delay in onset could reduce the prevalence of
ADbyalmost50%”[4],underscoringtheneedforadrugthatwilldelaythe
onset or progression of dementia. The prevalence projections for AD are in
starkcontrasttootherindicationssuchasheartdiseaseandcancer,whichare
projected to remain stable or actually decline over time. From 2000 to 2005,
death rates have declined for most major diseases—including heart disease,
breastcancer,andprostatecancer—whiledeathsfromADcontinuetotrend
upward,andareexpectedtoincrease44%by2025[5].
Another regrettable example of stagnation in the field of CNS therapies
comes from psychiatry, and is evidenced by the lack of novel antipsychotic
drugs to treat schizophrenia and other psychotic disorders. The three-phase
ClinicalAntipsychoticTrialsofInterventionEffectiveness(CATIE)study,one
ofthelongestdrugtrialseverconductedinpsychiatry,beganin2000anddata
wereanalyzedbeginningin2005.Inthattimeperiod,onlytwonewantipsy-
(cid:1) (cid:1)
choticdrugs(ziprasidone[marketedasGeodonR andZeldoxR]in2001and
(cid:1)
AbilifyR in 2002) were approved. Since then, only one other drug has been
approved for the treatment of schizophrenia—Janssen’s InvegaTM (paliperi-
done),whichwasapprovedin2006.Invegaisanoralextended-release(ER)
major active metabolite of risperidone and would not be considered to be a
novelmolecularentityornewmolecularentity(NME).
InthefirstphaseoftheCATIEstudy,1493patientswithschizophreniawere
recruited at 57 US sites and were randomly assigned to receive the antipsy-
chotics olanzapine (7.5–30 mg/day), perphenazine (8–32 mg/day), quetiap-
ine(200–800mg/day),orrisperidone(1.5–6.0mg/day)forupto18months.
Ziprasidone (40–160 mg/day) was added in 2002 following its approval by
the FDA. The study concluded that the majority of patients in each treat-
ment group discontinued due to inefficacy or intolerable side effects or for
otherreasons.Patientsonolanzapinehadthebestrecordforcontinuingtreat-
ment, but this treatment was associated with greater weight gain and in-
creasesinmeasuresofglucoseandlipidmetabolism.Overall,74%ofpatients
