1.Foundation of clinicaltrialsPrerequisites of newdrug developmentAll drugs have two sides of a coin:effectiveness and toxicity.Apotentialdrug hastohave beneficial effects that outweighanypotential harm,i.e,afavorablebenefit-to-harm balance.Thedauntingprocessofdevelopinganew intervention islong-term,complexinprocedureandethics,andexpensiveResearchofbiochemicalcompoundsPreclinical study:invitro,invivoandinsilicoPhaseItrial:clinicalpharmacologyandtoxicityPhaseIltrial:safety,effectivenessandoptimaldosagePhaseIlltrial:full-scaleevaluationofeffectiveness,safetyPhase IV trial: post-marketing surveillance, long-ternafetymyXikui Wang (University of Manitoba)Statistical DecisionAnalysis201324/198
1. Foundation of clinical trials Prerequisites of new drug development All drugs have two sides of a coin: effectiveness and toxicity. A potential drug has to have beneficial effects that outweigh any potential harm, i.e, a favorable benefit-to-harm balance. The daunting process of developing a new intervention is long-term, complex in procedure and ethics, and expensive. Research of biochemical compounds Preclinical study: in vitro, in vivo and in silico Phase I trial: clinical pharmacology and toxicity Phase II trial: safety, effectiveness and optimal dosage Phase III trial: full-scale evaluation of effectiveness, safety Phase IV trial: post-marketing surveillance, long-term safety Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 24 / 198
1.Foundation of clinical trialsTypes of drug agents:ocytotoxic:Mostoncologydrugsarecytotoxic,whichdamageordestroyrapidlygrowingcancercells.Forexample,carboplatinandpaclitaxeltypicallyshrinkthetumorin an increasing, dose-dependentmanner.cytostatic:Manycytostatictherapiesaredirectedatmoleculartargetstoinhibittumorgrowthorpreventtheproliferationof cancercells.Patientsmaybenefitfromcytostaticagentsevenwithoutshrinkingthetumor.Forexamplefor lung cancer,gefitinib prevents cancer cells fromgrowing andmultiplying.biologic:Biologicagentsaresubstancesfromalivingorganism.Forexample,interleukinsandvaccinesareoftenused intheprevention,diagnosisandtreatmentofcancerIRSITUMANITORandotherdiseases.Xikui Wang (Universityof Manitoba)Statistical Decision Analysis201325/198
1. Foundation of clinical trials Types of drug agents: cytotoxic: Most oncology drugs are cytotoxic, which damage or destroy rapidly growing cancer cells. For example, carboplatin and paclitaxel typically shrink the tumor in an increasing, dose-dependent manner. cytostatic: Many cytostatic therapies are directed at molecular targets to inhibit tumor growth or prevent the proliferation of cancer cells. Patients may benefit from cytostatic agents even without shrinking the tumor. For example for lung cancer, gefitinib prevents cancer cells from growing and multiplying. biologic: Biologic agents are substances from a living organism. For example, interleukins and vaccines are often used in the prevention, diagnosis and treatment of cancer and other diseases. Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 25 / 198
1.Foundation of clinical trialsA clinical trialisaprospective,controlled,randomized,experimentalstudytoassessthe efficacy of anewintervention in man,by comparingtheoutcomes in a group ofpatients treatedwith the interventionwith those observed in a comparable group of patients receivingacontroltreatment.Therearealwaystwosidestoacoin:minimizingbiases(experimental,statistical,systematicsetc.)maximizingethics(duringandaftertheclinicalresearch)Governmentapproval:USA:FoodandDrugAdministration(FDA)Canada:HealthCanadaSIT·China:TheStateFood andDrugAdministration(SFDAToa26/198Xikui Wang (Universityof Manitoba)StatisticalDecisionAnalysis2013
1. Foundation of clinical trials A clinical trial is a prospective, controlled, randomized, experimental study to assess the efficacy of a new intervention in man, by comparing the outcomes in a group of patients treated with the intervention with those observed in a comparable group of patients receiving a control treatment. There are always two sides to a coin: minimizing biases (experimental, statistical, systematics, etc.) maximizing ethics (during and after the clinical research) Government approval: USA: Food and Drug Administration (FDA) Canada: Health Canada China: The State Food and Drug Administration (SFDA) Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 26 / 198
1.Foundation of clinicaltrialsStrengthsofprospective,controlledclinicaltrials:Beingprospective:Everydetailofthestudyisplannedprospectively,andthedesigngivestheinvestigatorsbettercontrol overthe completenessand qualityofdata collectionandmonitoring.QualityofstudyisimprovedBeingcontrolled:Byusingcomparablegroups(interventionandcontrol)ofpatients,thereisbestchanceofestimatingbothfavorableandunfavorabletreatmentseffectsandofobjectivelydistinguishingbetweenrealtreatmenteffectsandthenatural course of disease.Thisminimizes theplaceboeffect and Hawthorneeffect.The controltreatmentcanbethestandardofcareoraplaceboAtrialis uncontrolled ifthereisno controltreatmentorifthenewtreatmentiscomparedwithhistoricalcontrols.JNIVERSITLMANITOSXikuiWang (UniversityofManitoba)Statistical Decision Analysis27/1982013
1. Foundation of clinical trials Strengths of prospective, controlled clinical trials: Being prospective: Every detail of the study is planned prospectively, and the design gives the investigators better control over the completeness and quality of data collection and monitoring. Quality of study is improved. Being controlled: By using comparable groups (intervention and control) of patients, there is best chance of estimating both favorable and unfavorable treatments effects and of objectively distinguishing between real treatment effects and the natural course of disease. This minimizes the placebo effect and Hawthorne effect. The control treatment can be the standard of care or a placebo. A trial is uncontrolled if there is no control treatment or if the new treatment is compared with historical controls. Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 27 / 198
1Foundation of clinical trialsStrengthsofrandomized,experimentalclinicaltrials:Beingrandomized:ThispreventsselectionbiasandeliminatessystematicdifferencesbetweenstudygroupsValid statistical comparisonisguaranteedandthe integrityoftheclinicalstudyisprotected.Beingexperimental:Theinterventionisinitiated bythe?investigators,notstartedby other peopleas inobservationalstudies.Thewrittenprotocolspecifiesallnecessarydetailsoftheintervention,includingpatientinclusionandexclusioncriteria,andexplicitdosageregimen,etc.JNIVERSIT.LMANITOSXikui Wang (University of Manitoba)Statistical DecisionAnalysis28/1982013
1. Foundation of clinical trials Strengths of randomized, experimental clinical trials: Being randomized: This prevents selection bias and eliminates systematic differences between study groups. Valid statistical comparison is guaranteed and the integrity of the clinical study is protected. Being experimental: The intervention is initiated by the investigators, not started by other people as in observational studies. The written protocol specifies all necessary details of the intervention, including patient inclusion and exclusion criteria, and explicit dosage regimen, etc. Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 28 / 198