Why Do Clinical Research.ppt

WhyDoClinicalResearch SatisfactionofansweringimportantquestionswhichwillimprovethehealthofourpatientsStatusofresearchersSkilladvancementProfessionaladvancementSalaryandJobSecurity WhatisResearch Researchistheendeavortodiscovernewfacts procedures methods andtechniquesbythescientificstudyofacourseofcriticalinvestigation ClinicalResearch Clinicalresearchinvolvesworkingwithhumansubjectstoanswerquestionsrelevanttotheirwell beingPatientorientedresearchiswherethe rubbermeetstheroad HowToDo Research StartwithdefiningthequestionWritedownaclearaimDividetheproblemintosmaller answerablequestions HowToDo Research DevelophypothesesDecidewhatdataisneededtotestthehypothesesRefinetheaboveandcheckthelineofthought GoodResearch CLEAREssentialforboththeproblemandtheanswerACCURATEExactnessandprecisioncomefromhardworkandresponsibleeffortRELIABLEIfrepeatedwilltheanswerbethesame GoodResearch OBJECTIVETheresearcherexposesallpossibleprejudicesattheonsetofthestudydesignandstrivestoovercomethemWilltheresearchbeuntarnishedbypersonalgain biases vestedinterests etc ResearcherQualities KnowledgeableObservantLogicalOpen mindedHonest MotivatedIndependentFlexibleCareful ResearcherQualities CuriousInquisitiveEagertolearnSkepticalPerceptive PersistentPatientOriginalCreative GettingStarted LearnyoursubjectRead Read ReadStartgeneralandthenfocusBeginwiththeproblem GettingStarted FormulatetheproblemasaresearchquestionReducethequestiontoasingleunambiguousquestionthatiswell definedandanswerable StagesinCreativity SENSERealizetheneedforastudyPREPAREGatherrelevantinformationINCUBATEThinkthroughtheproblemILLUMINATEImaginepossiblesolutionsVERIFYEvaluatethesolutionsyouhavegenerated Hypothesis ThesisisthepositionthatyoubelieverepresentstruthHypothesisisthefoundationontopofwhichyoubuildyourthesis Hypothesis HypothesisisatentativeconstructtobeprovedordisprovedaccordingtotheevidenceThehypothesisissometimesexpressedasanullhypothesis AGoodHypothesisShould BetestableConveythenatureoftherelationshipbeingtestedStateexactlywhatvariablesformthisrelationshipReflectallvariablesofinterestBeformulatedearlyonintheplanningstage StudyTypes Willyoutestahypothesisordescribeaphenomenon ObservationalLongitudinalCross sectionalRandomized double blind parallelgroup placebocontrolledtrial EpidemiologyvsRCT EpidemiologyallowsthestudyoftherealworldandthedevelopmentofhypothesisregardingdiseasestatesRandomized controlledtrialsallowtherigoroustestingofhypothesisinawellcharacterizedmannerthatislessrealworldinnature StudyDesign StudyPopulationAgeGenderEthnicity RaceDiseasecharacteristicsExclusionsNumberStratificationRandomization HumanSubjects ThesafetyandrightsofhumansubjectsmustbeprotectedStudyDesignInstitutionalReviewBoardInformedconsentDataSafetyMonitoring MedicalMonitors KeyQuestions Whatisthemainpurposeofthetrial Whattreatmentswillbeusedandhow Whatistheparticipantrisk Whatarethepossiblebenefits Howwillpatientsafetybemonitored KeyQuestions Aretherealternativetreatments Whoissponsoringthetrial Whatistheparticipantburden Howlongandwhere Whatdotheparticipantshavetodo Willtherebeanydiscomfortevenifthereisnorisk Methods DefinemethodscarefullyDecreasevariabilityCheckreliability reproducibilityAreyoutestingwhatyouthinkyouaretesting Methods Tryto walkthrough thestudyandconsiderasmanylikelyscenariosaspossible Trytodesigninanyvariationsintreatmentordatacollectionthatyouthinkwilloccurbeforethestudystarts OperationalizeConcepts SpecifyhowyouwillrepeatablyandreliablymeasurethevariablesyouareusingtoanswerthequestionAnoperationaldefinitionspecifieshowyourconceptswillbeobservedandmeasuredThisshouldallowyourresearchtobereproduced Data DataarethefactsyoumeasureTheyshouldbecarefullyrecordedinanunbiasedmannerTheyshouldbemeasuredinamannerthatminimizesrandomvariationTheyshouldbederivedfromtheoperationaldefinitionsyouhavedeveloped DataValidation Dothedatamakesense LookcriticallyatthedataHighestandlowestvaluesDataentryerrorsDistribution NormalorskewedCheckselecteddataentrieswithoriginaldataforms DataInterpretation Donotinterpret analyzedatauntilafterstudyiscompletedDonot unblind subjectsuntilthestudyiscompletedotherthanforsafetyreasonsDonotinterpret analyzedatauntilafterdatahasbeenvalidatedandthedatasetclosed DataInterpretation UsetheresearchquestionandhypothesestoguideanalysesUseaprioridefinitionsforanysub setanalysesExplorationofepidemiologicdatasetsisOK butneedtoavoiddatamining WritingItUp Ifyoudon twriteit thenitdidn thappenOrderofwriting MethodsResultsIntroductionDiscussionAbstractTitle WritingItUp Afterthefirstdraft newanalyseswillusuallybesuggestedbytheprocessofputtingyourideasdownonpaperPutthepaperawayforafewweeksandthenreaditagainAskmentorsandcolleaguestoreadthepaperatthefirstdraftstage SendingItIn Whenwritingthepaper havethejournalyouwillsubmittoinmindPickjournalsthatwillmatchyourpaper stopicandthequalityandimportanceofyourworkAimhighand ifneeded golowPersist Persist Persist ClinicalResearch DrugDevelopment DrugDevelopment Preclinical LaboratoryStudyCellcultureinanimalandhumancellsAnimalstudiesLookingbothattoxicity carcinogenicityaswellaseffect ifrelevantDevelopInvestigationalNewDrugapplicationwithFDA IND PhaseIStudies AssessdrugsafetyandtolerabilityHealthyvolunteers thenthosewithtargetdiseasePharmacokineticsAbsorptionMetabolismExcretionDoseescalation70 ofnewdrugspassthisphase PhaseIIStudies AssessdrugefficacyUsuallyrandomized controlledtrialswithsmallernumbersuptoseveralhundredsubjectsTestdifferenttherapeuticstrategiesUsesurrogatevariablesandareusuallyshorttermOnly1 3getpastphaseII PhaseIIIStudies LargescaleRCTtoassessefficacyandsafetyofmedicationSeveralhundredtothousandsofpatientsenrolledClassicrandomized placebo controlleddesignLong termstudydesignwithrealworldoutcomevariablesDefinepackageinsertcontentandallowmarketing StudySizeandAdverseEvents Thesizeofthetreatmentgroupdeterminesthelikelyfrequencyofadverseevents sideeffects thatcanbedetectedAgoodruleofthumbisthatyoucandetectanadverseeventratethatisoneeventinthenumberofsubjectsdividedbythree Astudywith100patientswillonlydetectAE sthatoccuratarateof1 33 3 PhaseIVStudies ComparedrugswithotherdrugsonthemarketDefinebroadertargetpopulationMonitorlong termefficacyandsafetyConducthealtheconomicsassessmentandqualityoflifestudy ReadingClinicalResearch HowtoApproachRCTReports ReadingClinicalTrials Allthatglittersisnotgold byBengtandCurtFurbergJustbecauseastudyispublishedinajournaldoesnotmeanthatitrepresentstruth Throwaways andDrugcompanysponsorednewslettershaveeithernoorlimitedpeerreview WasthequestionstatedAPriori Exploringdataisacceptabletodefinehypotheses butcannotdefinitivelyanswerthemPrimaryoutcomesandlimitedsecondaryoutcomesshouldbecarefullydefinedbeforestudycommences WasthequestionstatedAPriori MultiplehypothesistestingcanleadtofalseassociationP 0 05issubvertedifthereare20looksatthedata Isthequestionrelevant Doestheanswerclarifywhetherthetreatmentwillhelppatientsto FeelbetterLivelongerHavelesscomplicationsofillnessAretheendpointsrealworldormerelysurrogatesHowcanonegeneralizethefindings Howisimprovementquantified Aretheoutcomesrelevant Dothemeasuresusedmakesense Isthemagnitudeofthedifferencerelevanttopatientcare Isthestudy over powered Aretheoutcomesrelevant QualityoflifeMortalityHealtheconomicsSurrogatemarkersofclinicaloutcomeSurrogatebiologicmarkers Howareadverseeventsmeasured Sideeffectsarecharacterizedas Severe Treatmentmustbestopped orpatienthospitalized ordies ordevelopscancer orhascongenitalanomalyinchildModerate Dosagemustbereduced usuallyleadstodiscomfort temporarydisability orreductioninfunctioningMild Nochangeintreatment Limiteddiscomfortordysfunction Howareadverseeventsmeasured AE sarecharacterizedastowhetherornottheyarerelatedtothemedication DefinitelyLikelyProbablyPossiblyNotassociated Arethepatientsrepresentative ThisismostproblematicinpediatricswhereweoftenhavetoextrapolatefromadultstudiesGender age andracecanallalteroutcomesDiseaseclassificationandseveritycanalteroutcomesHighriskpatientsareusuallyexcluded Wherethegroupsinitiallycomparable Eveninstudiesof150 200subjectssubstantiveimbalancecanoccurbetweentreatmentgroupsWasstratificationusedtoensurebalance Didthetreatmentgroupstartoutsickersothattheylikelyw