Clinical Trials in Rheumatoid Arthritis and Osteoarthritis PDF
Preview Clinical Trials in Rheumatoid Arthritis and Osteoarthritis
Clinical Trials in Rheumatoid Arthritis and Osteoarthritis SeriesEditors DerekPearson,BSc,PhD ColinG.Miller,PhD,FICR JointServiceManager SeniorVicePresident MedicalPhysics&ClinicalEngineering MedicalAffairs Department Bio-ImagingTechnologiesInc. NottinghamUniversityHospitalsNHS 826Newtown-YardleyRoad Trust Newtown,PA18940 CityHospitalsCampus USA HucknallNG51PB UK OtherTitlesinThisSeries ClinicalTrialsinOsteoporosis(2ndEdition) DerekPearsonandColinG.Miller ClinicalTrialsinRheumatoidArthritisandOsteoarthritis DavidM.ReidandColinG.Miller • David M. Reid Colin G. Miller Editors Clinical Trials in Rheumatoid Arthritis and Osteoarthritis 123 Editors DavidM.Reid,MBChB,MD,FRCP ColinG.Miller,BSc,PhD,FICR DepartmentofMedicineandTherapeutics Bio-ImagingTechnologiesInc. UniversityofAberdeen Newtown,PA,USA Aberdeen,UK ISBN:978-1-85233-874-9 e-ISBN:978-1-84628-742-8 DOI:10.1007/978-1-84628-742-8 BritishLibraryCataloguinginPublicationData Clinicaltrialsinrheumatoidarthritisandosteoarthritis 1.Rheumatoidarthritis-Treatment2.Osteoarthritis- Treatment3.Clinicaltrials I.Reid,David,1951-II.Miller,ColinG.,1960- 616.7’22060724 ISBN-13:9781852338749 LibraryofCongressControlNumber:2007937490 (cid:2)c2008Springer-VerlagLondonLimited Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permittedundertheCopyright,DesignsandPatentsAct1988,thispublicationmayonlybereproduced, storedortransmitted,inanyformorbyanymeans,withthepriorpermissioninwritingofthepublish- ers,orinthecaseofreprographicreproductioninaccordancewiththetermsoflicencesissuedbythe CopyrightLicensingAgency.Enquiriesconcerningreproductionoutsidethosetermsshouldbesentto thepublishers. Theuseofregisterednames,trademarks,etc.inthispublicationdoesnotimply,evenintheabsenceofa specificstatement,thatsuchnamesareexemptfromtherelevantlawsandregulationsandthereforefree forgeneraluse. Productliability:Thepublishercangivenoguaranteeforinformationaboutdrugdosageandapplication thereofcontainedinthisbook.Ineveryindividualcasetherespectiveusermustcheckitsaccuracyby consultingotherpharmaceuticalliterature. Printedonacid-freepaper 987654321 SpringerScience+BusinessMedia springer.com Contents Contributors ..................................................... vii 1 Introduction ................................................... 1 DavidM.ReidandColinG.Miller 2 Historical and Current Perspectives on Management of OsteoarthritisandRheumatoidArthritis.......................... 5 ShirishDubeyandAdewaleO.Adebajo 3 DevelopmentofBiologicalTherapiesforInflammatoryArthritis..... 37 NeilBasu 4 StudyDesignandEndPointsforRheumatoidArthritisTrials ....... 51 PieterGeusensandColinG.Miller 5 Study Design and End Points in Ankylosing Spondylitis ClinicalTrials.................................................. 69 DésiréevanderHeijde 6 TrialDesignandOutcomesinOsteoarthritis....................... 81 NigelArden 7 EthicalConsiderations .......................................... 91 DerekPearsonandColinG.Miller 8 OrganizationoftheClinicalTrialbytheSponsor ..................113 ColinG.Miller 9 OrganizationoftheTrialattheInvestigatorSite ...................123 JulieShotton,DavidM.Reid,andColinG.Miller 10 RoleoftheImagingCoreLaboratoryinRheumatoidArthritisand OsteoarthritisClinicalTrials.....................................135 MarkD.EndresandAnnaM.Baratelle 11 BiochemicalMarkersofRheumatoidArthritisandOsteoarthritis: ClinicalUtilityandPracticalConsiderations.......................151 MarioR.EhlersandElizabethT.Leary v vi Contents 12 DataAnalysisandPresentation:WritingaPaperforPublication ....171 DerekPearson 13 RadiographicImagingEndPointsinRheumatoidArthritisTrials....201 AnnaM.BaratelleandDésiréevanderHeijde 14 RadiographyinClinicalTrialsInvestigatingOsteoarthritis..........223 CornelisvanKuijk 15 Use of Quantitative Magnetic Resonance Imaging in the Cross-SectionalandLongitudinalEvaluationofStructuralChanges inKneeOsteoarthritisPatients...................................235 Jean-Pierre Raynauld, Johanne Martel-Pelletier, François Abram, andJean-PierrePelletier 16 BiochemicalMarkersasSurrogateEndPointsofJointDisease ......249 L.StefanLohmanderandDavidR.Eyre 17 RoleofGeneticsandGenomicsinClinicalTrialsinOsteoarthritis andRheumatoidArthritis .......................................275 StuartH.Ralston 18 Cost-Effectiveness of New Biologics for Rheumatoid Arthritis andOsteoarthritis ..............................................289 YolandaBravoVergelandDavidTorgerson Abbreviations......................................................309 Index .............................................................311 Contributors AdewaleO.Adebajo,MBBS,MSc,FRCP HonorarySeniorLecturer,AcademicRheumatologyGroup,UniversityofSheffield, SheffieldUK FrançoisAbram,PhD ArthroVisionInc.,Montreal,Canada NigelArden,MBBS,MSc,MD Senior Lecturer in Rheumatology, MRC Unit, Southampton General Hospital, Southampton,UK AnnaM.Baratelle,ASRT,(R)(MR) Clinical Imaging Lead, Centocor, Malvern, Pennsylvania, USA. Previously, Director, Business Development and Clinical Education, Bio-Imaging Technologies,Inc.,Newtown,Pennsylvania,USA NeilBasu,MBChB(Hons),MRCP(UK) SpecialistRegistrar,NHSGrampian,AberdeenRoyalInfirmary,Aberdeen,UK YolandaBravoVergel,BA,MA,MSc ResearchFellow,CentreforHealthEconomics,UniversityofYork,York,UK ShirishDubey,MB,BS,MRCP(Ireland),DMedEd PreviouslyClinicalLecturerinRheumatologyandMedicalEducation,Academic UnitofMedicalEducation,UniversityofSheffield,Sheffield,UK MarioR.Ehlers,MD,PhD ChiefMedicalOfficer,PacificBiometrics,Inc.,Seattle,Washington,USA MarkD.Endres,BS,CNMT VicePresident,GlobalBusinessDevelopment,Bio-ImagingTechnologies,Inc., Newtown,Pennsylvania,USA DavidR.Eyre,BS,PhD Department of Orthopaedics and Sports Medicine, University of Washington, Seattle,Washington,USA PieterGeusens,MD,PhD DepartmentofRheumatology,UniversityHospital,Maastricht,TheNetherlands andBiomedicalResearchInstitute,UniversityHasselt,Diepenbeek,Belgium vii viii Contributors ElizabethT.Leary,PhD ChiefScientificOfficer,PacificBiometrics,Inc.,Seattle,Washington,USA L.StefanLohmander,MD,PhD Institute of Clinical Sciences, Department of Orthopaedics, Lund University Hospital,Lund,Sweden JohanneMartel-Pelletier,PhD Osteoarthritis Research Unit, Notre-Dame Hospital, University of Montreal HospitalCentre(CHUM),Montreal,Canada ColinG.Miller,BSc,PhD,FICR SeniorVicePresident,MedicalAffairs,Bio-ImagingTechnologiesInc.,Newtown, Pennsylvania,USA DerekPearson,BSc,PhD ClinicalDirector,MedicalPhysics,CityHospital,Nottingham,UK Jean-PierrePelletier,MD Osteoarthritis Research Unit, Notre-Dame Hospital, University of Montreal HospitalCentre(CHUM),Montreal,Canada StuartH.Ralston,MD,FRCP,FMedSci,FRSE HeadofSchoolofMolecularandClinicalMedicine&ProfessorofRheumatology, MolecularMedicineCentre,UniversityofEdinburgh,Edinburgh,UK Jean-PierreRaynauld,MD,FRCPC Osteoarthritis Research Unit, Notre-Dame Hospital, University of Montreal HospitalCentre(CHUM),Montreal,Canada DavidM.Reid,MBChB,MD,FRCPedin,FRCPlon Professor of Rheumatology, Head of Department of Medicine & Therapeutics, UniversityofAberdeen,Aberdeen,UK JulieShotton,BSc PreviouslySeniorResearchNurse,OsteoporosisResearchUnit,Departmentof Medicine&Therapeutics,UniversityofAberdeen,Aberdeen,UK DavidTorgerson,MSc,PhD DirectorofYorkTrialsUnit,DepartmentofHealthSciences,UniversityofYork, York,UK DésiréevanderHeijde,MD,PhD Professor of Rheumatology, Leiden University Medical Center, Department ofRheumatology,Leiden,TheNetherlands CornelisvanKuijk,MD,PhD DepartmentofRadiology,VUUniversityMedicalCenter,Amsterdam, TheNetherlands Chapter1 Introduction DavidM.ReidandColinG.Miller Why a Book About Clinical Trials in Rheumatoid Arthritis andOsteoarthritis? From an etiology of disease perspective, a book on rheumatoid arthritis (RA) and osteoarthritis(OA)isastrangecombination;however,fromaclinicaltrialperspec- tive,theprimaryendpointsareverysimilar.Theprimaryendpointsinbothdisease states are imaging and serum or urine biomarkers as recognized by the U.S. Food andDrugAdministration(FDA)TheFDAguidancedocumentsforOA[1]referto the RA guidance documents for the imaging end points [2]. During the writing of thisbook,theOsteoarthritisResearchSocietyInternational(OARSI)hasteamedup withtheOutcomesMeasuresandEvaluationinRheumatoidArthritisClinicalTrials (OMERACT)tocreatetheOMERACT-OARSIworkinggroup.Thisisanobvious recognitionofsimilarendpointsofthediseasestates. TheevolutionofthetrialsinRAandOAisataninterestingpointintime.There have been a number of successful therapeutic disease-modifying agents that have been developed and are now on the market for RA. The same is not true for OA, where at the time of writing there have been no successful FDA submissions for a disease modifying osteoarthritis anti-rheumatic drug (DMOARD), partly due to a lack of compounds and partly due to the challenges of running the trials. With RA,thereisnowastandardpatternandexpectationforperformingthesetrialswith threeanti-TNF-(cid:2)andoneanti-B-cellmonoclonalantibodyproductsonthemarket in a number of indications and many more to follow. For OA, the one large trial testingapotentialDMOAD,usingthebisphosphonaterisedronate[3],sadlymissed its primary end point. There are now a handful of studies evaluating glucosamine andchondroitinsulfateinboththeUnitedStatesandEurope[4,5].Thefirstresults are not only suggestive of a potential positive outcome but also more importantly demonstratethatwithcarefulcontrols,astudyinOAlookingatjointspacenarrow- ingcanbeachieved(seeChapter14). D.M.Reid Professor of Rheumatology, Head of Department of Medicine & Therapeutics, University of Aberdeen,Aberdeen,UK D.M.Reid,C.G.Miller(eds.),ClinicalTrialsinRheumatoidArthritisandOsteoarthritis, 1 (cid:2)c Springer-VerlagLondonLimited2008 2 D.M.Reid,C.G.Miller OAisacripplingdiseasethathasapproximately10timestheprevalenceofRA, andthereisahugeunmetmedicalneedforgooddrugstohaltdiseaseprogression. ThisisnottominimizethepainofRA;rather,thelessonslearnedfromtheRAfield canbeappliedtoOA. Clinicaltrialsarerequiringmoreandmorerigor,andthespecificendpointsare becomingmorecomplex,withanincreasingandbewilderingnumberofregulatory hurdles.ThisisthecasewithtrialsinRAandOA.Thesimilarityofdesignmakes thetherapeuticcombinationcometogether.Thisbookisintendedforthosenewto conductingclinicaltrialsintheseareas:ahandbookora“howto.”Itisnotintended asanall-encompassingtextontheresultsofthosestudiesthathavegonebeforeor a thorough in-depth analysis of how to get through the regulations like the Code ofFederalRegulations(CFR21Part11,ElectronicRecordsandUseofElectronic Signatures) [6]. This is the second book in the series (the first one being Clinical Trials on Osteoporosis) and it follows a similar format, allowing the reader to be abletoreadeachchapterinisolationortoputthepiecestogethertoobtainanoverall picture.Aswiththebookonosteoporosis,thisbookisalsouniqueinthatitbrings togetherboththeclinicaltrialaspectandthetherapeuticaspectintoonevolume. HowThisBookWorks Theaimofthisbookistoleadtheresearchthroughallthestagesofaclinicaltrial. The first part covers background to current and some future therapies for RA and OA(Chapters and3),andthesecondpartexaminesstudydesign(Chapters4to7) and the pretrial phase including ethical considerations specific to trials in RA and OA(Chapter7). Thethirdpart(Chapters8to11)looksattheday-to-dayrunningofthetrialfrom thefourmainconstituentsinvolvedinpatientcollectionanddatamanagement:the sponsor,thesite,thecentralbloodorbiomarkerlab,andthecentralimagingcorelab. Itisinterestingtonotethattheprimaryendpointsofbiomarkers,betheyserologic or imaging, are all now processed through independent third-party groups as a de factostandard.Thiswouldnothavebeenthecase15yearsago. Thefourthpart(Chapter12)coversdataanalysisandpresentationandincludesa guidetowritingapaperforapeer-reviewedjournaltoastandardthatwillensurethat readerswillgainfullbenefitfromone’strialandtheresultswillbeeasilyincluded intosubsequentmeta-analyses. The final part examines imaging end points and biochemical markers for both RAandOA(Chapters13to16)anddescribesnewpossibleendpointsofpharma- cogenomics(Chaper17)andpharmacoeconomics(Chapter18). We have attempted to use standard terminology throughout the book. This includes the sponsor (usually a pharmaceutical company who is funding the research),thecontractresearchorganization(orCRO),whichisacompanyrespon- sible for administering the trial, assuring the quality of the data, analyzing the data, and producing the final report. A clinical research associate (CRA) is the
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