1.Foundation of clinical trialsStrengthsofblinding/masking:Blinding/maskingpreventsselectionandresponsebiasesExampleofaplacebo-controlled,doubleblinded,9-monthvitaminCtrialforthepreventionandtreatmentofthecommoncold,conductedamong3ooemployeesoftheNational InstituteofHealth(Karlowskietal.1975):Themeandurationofcoldsamongthosewhodidnotbreaktheblindwassimilartothatoftheplacebogroup.Themeandurationof colds amongthosewhoknewtheyweretakingvitamin C was shorter than that of the placebo group.The gold standard: prospective, controlled, randomized, andblindedexperiment!福JNIVERSITYIMANITOAXikui Wang (University of Manitoba)Statistical Decision Analysis201329/198
1. Foundation of clinical trials Strengths of blinding/masking: Blinding/masking prevents selection and response biases. Example of a placebo-controlled, double blinded, 9-month vitamin C trial for the prevention and treatment of the common cold, conducted among 300 employees of the National Institute of Health (Karlowski et al. 1975): The mean duration of colds among those who did not break the blind was similar to that of the placebo group. The mean duration of colds among those who knew they were taking vitamin C was shorter than that of the placebo group. The gold standard: prospective, controlled, randomized, and blinded experiment! Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 29 / 198
1.Foundation of clinicaltrialsAll clinical trials have an inherent weaknessrelatedtotheassessmentof safetyandabalancebetweenbenefitandharmmustbeachievedWeaknessesofrandomizedcontrolledclinicaltrials:ManyPhase lllareunabletodetectunexpectedadverseevents.Terfenadine(Teldanex)hadbeenonthemarketforthanadecadebeforethedetection of aserious interactionwitherythromycinorgrapefruit juicethat could causeafatalarrhythmia.SomePhaseIllclinicaltrialsareunethical.TheAzTtrialandtheECMOtrialareclearexamples.Ontheotherhandthe exclusion ofpregnant womenfrom clinicaltrials of newdrugscreatesaninformationvacuum.NIVERSIT福IMANITOSXikui Wang (University of Manitoba)StatisticalDecision Analysis30/1982013
1. Foundation of clinical trials All clinical trials have an inherent weakness related to the assessment of safety and a balance between benefit and harm must be achieved. Weaknesses of randomized controlled clinical trials: Many Phase III are unable to detect unexpected adverse events. Terfenadine (Teldanex) had been on the market for than a decade before the detection of a serious interaction with erythromycin or grapefruit juice that could cause a fatal arrhythmia. Some Phase III clinical trials are unethical. The AZT trial and the ECMO trial are clear examples. On the other hand, the exclusion of pregnant women from clinical trials of new drugs creates an information vacuum. Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 30 / 198
1Foundation of clinical trialsRelatedhistory:In1600,Lancaster,acaptainofashipfortheEastIndianShippingCompany,conducted anunplannednaturalexperiment to examine the effect of lemon juice on scurvyfor sailers (Bull 1959).In1747,JamesLindconductedaplannedexperimentonthe treatment of scurvy withan untreated control group(Lind1753).Therewere12sailers,withtwopatientspertreatment.Thetwo sailers withlemons and orangesrecovered.In1799,Haygarthconductedanexperimentusingashamprocedure (Haywarth 1800).In1800,asmallpoxtrialswascarriedoutinU.S.(Waterhouse1800,1802)福JNIVERSITMANITONXikui Wang(UniversityofManitoba)Statistical Decision Analysis201331/198
1. Foundation of clinical trials Related history: In 1600, Lancaster, a captain of a ship for the East Indian Shipping Company, conducted an unplanned natural experiment to examine the effect of lemon juice on scurvy for sailers (Bull 1959). In 1747, James Lind conducted a planned experiment on the treatment of scurvy with an untreated control group (Lind 1753). There were 12 sailers, with two patients per treatment. The two sailers with lemons and oranges recovered. In 1799, Haygarth conducted an experiment using a sham procedure (Haywarth 1800). In 1800, a smallpox trials was carried out in U.S. (Waterhouse 1800, 1802). Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 31 / 198
1.Foundation of clinical trials丰佳UNIVERSITYALMANITOAAXikui Wang (Universityof Manitoba)Statistical Decision Analysis201332/198
1. Foundation of clinical trials Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 32 / 198
1.Foundation of clinical trialsRelated history:In1834,Louisdescribedtheprocessofkeepingtrackofoutcomesofclinical trials andthe needfor consideringthepatients'riskfactors,andthenatural historyofthedisease(Louis 1938).In1863,theplacebotreatmentwasusedforthefirsttime(Sutton 1865).In1887,theNationalInstituteofHealthstarteditstrace.In1923,Fisherappliedtheprincipleof randomizationtoexperimentation(FisherandMacKenzie1923)In1931,aspecialcommitteeonclinicaltrialswascreatedbytheMedicalResearchCouncil(MRC)ofGreatBritain(MedicalResearchCouncil1931)超UNIVERSITYLMANITOAXikui Wang (University of Manitoba)Statistical Decision Analysis201333/198
1. Foundation of clinical trials Related history: In 1834, Louis described the process of keeping track of outcomes of clinical trials and the need for considering the patients’ risk factors, and the natural history of the disease (Louis 1938). In 1863, the placebo treatment was used for the first time (Sutton 1865). In 1887, the National Institute of Health started its trace. In 1923, Fisher applied the principle of randomization to experimentation (Fisher and MacKenzie 1923). In 1931, a special committee on clinical trials was created by the Medical Research Council (MRC) of Great Britain (Medical Research Council 1931). Xikui Wang (University of Manitoba) Statistical Decision Analysis 2013 33 / 198