clinicaltrials临床试验方案培训ppt课件

clinicaltrials临临床床试试验验方案方案clinicaltrials临床试验方案1Overview Purpose of Research Studies Classifications of Epidemiological Research Basic Research Terminology Features of Clinical TrialsDesign/ProtocolPhases of a StudyEthics Protection of Participants Contributions of Clinical TrialsParticipating in a TrialConclusion&Take Home Messageclinicaltrials临床试验方案2Overview Purpose of ResearchOverview to Research StudiesWhy Do Research Studies?To collect data on usual and unusual events,conditions,&population groupsTo test hypotheses formulated from observations and/or intuitionUltimately,to understand better ones world and make“sense of it”clinicaltrials临床试验方案3Overview to Research StudiesWhOverview to Research StudiesVarious types of research studies Many classified as“Epidemiological Studies”Epidemiology often is defined as:The study of the distribution of a disease or condition in a population and the factors that influence that distribution.clinicaltrials临床试验方案4Overview to Research StudiesVaClassifications of Research Studies:Three Main TypesObservational Studies:Observational Studies:Groups are studied&contrasts made between groups The observed data collected are analyzedAnalytic Studies:Analytic Studies:Also called Experimental Study the impact of a certain therapy Ultimately the investigator controls factor being studiedClinical Trial:Clinical Trial:Considered the“true”experimental study“Gold Standard”of clinical researchOften a prospective study that compares the effect and value of an intervention against a control in human subjects clinicaltrials临床试验方案5Classifications of Research StAnother Classification SystemNon-directed Data Capture Ex:Vital StatisticsDirected Data Capture&Hypothesis Testing Ex:Cohort Studies,Case Control StudiesClinical Trials Ex:Investigation of Treatment/Condition Ex:Drug Trialsclinicaltrials临床试验方案6Another Classification SystemThe Different Study DesignsCase-control CohortCase Reports Case SeriesOutcomes Based:Survey Research:Quality of LifeQuestionnairesDecision analysis Polls Economic AnalysisSurveysMeta AnalysesSurvival AnalysisRandomized Clinical Trialclinicaltrials临床试验方案7The Different Study DesignsCasBasic Research TerminologyRetrospective:Refers to time of data collectionProspective:Refers to time of data collectionCase Control Study:Persons w/disease&those w/out are comparedCohort Study:Persons w/and/or w/out disease are followed over timeclinicaltrials临床试验方案8Basic Research TerminologyRetrTerminology(Cont.)Cross-sectional Study:Presence or absence of exposure to possible risk factor measured at one point in time.Prevalence obtained.Prevalence:The#of new cases and existing cases during specified time period.Incidence:The#of NEW cases per unit of a population at risk for disease occurring during stated time period.clinicaltrials临床试验方案9Terminology(Cont.)Cross-sectiHistorical MinuteFirst“Clinical Trials”Clinical Trials have a long history even if not acknowledged as Clinical trialsFormal record of clinical trials dates back to the time of the“Trialists”:Dr.Van Helmonts proposal for a therapeutic trial of bloodletting for fevers 1628Dr.Linds,a ship surgeon,trial of oranges&limes for scurvy 1747 clinicaltrials临床试验方案10Historical MinuteFirst“CliniHistorical MinuteFirst“Clinical Trials”Historical Highlights of Drug Trials1909:Paul Ehrlich-Arsphenamine1929:Alexander Fleming-Penicillin1935:Gerhard Domagk-Sulfonamide1944:Schatz/Bugie/Waksman StreptomycinBy 1950,the British Medical Res.Council developed a systematic methodology for studying&evaluating therapeutic interventionsclinicaltrials临床试验方案11Historical MinuteFirst“CliniCore Components of Clinical TrialsInvolve human subjectsMove forward in timeMost have a comparison CONTROL groupMust have method to measure interventionFocus on unknowns:effect of medicationMust be done before medication is part of standard of careConducted early in the development of therapiesclinicaltrials临床试验方案12Core Components of Clinical TrCore Components of Clinical TrialsMust review existing scientific data&build on that knowledgeTest a certain hypothesisStudy protocol must be built on soundðical scienceControl for any potential biasesMost study medications,procedures,and/or other interventions clinicaltrials临床试验方案13Core Components of Clinical TrThe Possible World of Clinical Trial DesignsRandomized/blinded trialRandomized/double blinded trialNon-randomized concurrent controlled trialPlacebo trialHistorical controlled trialCrossover TrialWithdrawal trialclinicaltrials临床试验方案14The Possible World of ClinicalSimplifiedRandomized:Randomized:Schemes used to assign participant to one groupEx:Every 3 gets higher doseNonrandomized:Nonrandomized:All with Hep.C=cases;others=controlsProtocol:Protocol:Study design-instructionsBlinded:Blinded:Participants do not know if in experimental or control groupDouble Blinded:Double Blinded:Participants AND staff do not know group assignmentPlacebo:Placebo:Inactive pill w/no therapeutic valueclinicaltrials临床试验方案15SimplifiedRandomized:Schemes Components of Clinical Trial Protocols Investigating two or more conditions so have two(+)groupsEx:drug vs.placebo;medicine vs.surgery;low dose vs.high doseSpecific inclusion/exclusion criteriaSample size&power calculationsPlan re:potential biasesPlan re:handling of attrition/loss to follow up clinicaltrials临床试验方案16Components of Clinical Trial PStudy Participant RecruitmentIdentify eligible participantsExplain studyProvide informed consentReassess eligibilityAssign to one groupParticipants should be told:May have side effects(adverse effects)Time commitmentBenefits&risksMay withdraw at any timeEnrollment 100%voluntary clinicaltrials临床试验方案17Study Participant RecruitmentIPhases of Clinical TrialsMost trials that involve new drugs go through a series of steps:#1:Experiments in the laboratory#2:Once deemed safe,go through 1-4 phasesclinicaltrials临床试验方案18Phases of Clinical TrialsMost Phases of Clinical TrialsPhase I:Small group 20-80 for 1st time to evaluate safety,determine safe dosage range&identify SEPhase II:Rx/tx given to larger group 100-300 to confirm effectiveness,monitor SE,&further evaluate safetyclinicaltrials临床试验方案19Phases of Clinical TrialsPhasePhases of Clinical Trials(cont.)Phase III:Phase III:Rx/tx given to even larger group 1,000-3,000 to fulfill all of Phase II objectives&compare it to other commonly used txs&collect data that will allow it to be used safelyPhase IV:Phase IV:Done after rx/tx has been marketed-studies continue to test rx/tx to collect data about effects in various populations&SE from long term use.clinicaltrials临床试验方案20Phases of Clinical Trials(conSummary of Phases I-III#Subs.#Subs.LengthLengthPurposePurpose%Drugs%Drugs Successfully Successfully TestedTestedPhase IPhase I20 100Several monthsMainly Safety70%Phase IIPhase IIUp to several 100Several months-2 yrs.Short term safety;mainly effectiveness33%Phase Phase IIIIII100s several 10001-4 yrs.Safety,dosage&effectiveness25-30%clinicaltrials临床试验方案21Summary of Phases I-III#Subs.Ethics of Clinical Trials:Protection of Participants3 ethical principles guide clinical research:Respect for Persons:Treatment of person as autonomousBeneficence:Issue re:potential conflict between good of society vs.individualJustice:Treatment of all fairly&all equally share benefits&risksclinicaltrials临床试验方案22Ethics of Clinical Trials:PrEthical Norms of Clinical TrialsSound study designs take into account:Randomization or sharing of risksProper use of placebo Processes to monitor safety of rx/txCompetent investigatorsInformed consentEquitable selection of participantsCompensation for study related injuriesclinicaltrials临床试验方案23Ethical Norms of Clinical Triaclinicaltrials临床试验方案培训ppt课件24Human Subjects ProtectionIRB responsible for such tasks:IRB responsible for such tasks:Review research to ensure that potential benefits outweigh risksDevelop and issue written procedures Review research for risk/benefit analysis&proper protection of subjectsIssue written notice of approval/disapproval to the InvestigatorReview and respond to proposed protocol changes submitted by the Investigatorclinicaltrials临床试验方案25Human Subjects ProtectionIRB Human Subjects ProtectionReview reports of deaths,and serious and unexpected adverse events received from the InvestigatorConduct periodic continuing review of the study,study risks,selection of subjects,privacy of subjects,confidentiality of data,and the consent processIRB Responsibilities(continued):clinicaltrials临床试验方案26Human Subjects ProtectionReviHistorical Minute:Origin of IRBs&Human Subject CodeAttention to protecting participants began after WWII w/the Nuremberg Trials(1947)Out of those trials,key points were codifiedclinicaltrials临床试验方案27Historical Minute:Origin of IHistorical Minute:10 Key PointsVoluntary informed consentExperiment must be for the good of society,&results not obtainable by other meansExperiment should be based upon prior animal studies Physical&mental suffering&injury should be avoidedNo expectation that death/disabling injury will occur from the experimentRisk vs.benefitProtect subjects against injury,disability,or deathOnly scientifically qualified persons to be involvedSubject can terminate her/his involvementclinicaltrials临床试验方案28Historical Minute:10 Key PoinHistorical Minute:Origin of IRBs&Human Subject CodesSince 1947,additional subject protection requirements developed&implemented Latest additions:Year 2000-President Clinton&DHHS Secretary Shalala announced additional study requirements related to:informed consenttraining req.adverse eventsconflict of interest civil monetary penaltiesimproved monitoring of Phase I&II trialsclinicaltrials临床试验方案29Historical Minute:Origin of Informed Consent:A Part of Human Subject ProtectionObjectives of Informed ConsentTo Ensure:VoluntarinessComprehensionInformationTo Demonstrate That:Person freely gave consent to participateConsent given by a competent person Person has been given all information Person knows this is research not treatmentclinicaltrials临床试验方案30Informed Consent:A Part of HuComponents of Informed ConsentMust Include the Following Information:Why research being done?What researchers want to accomplishWhat will be done and for how longRisks&benefits of trialOther treatments availableCan withdraw from trial whenever desireCompensation for unexpected injuriesclinicaltrials临床试验方案31Components of Informed ConsentVulnerable PopulationsGroups thought not to have autonomy to give informed consent:childrenmentally impaired,individuals with dementiaPrisonersOR OR Who may be unduly influenced to participate:studentssubordinatespregnant women(actually,the fetuses)patients(care-giver vs.researcher)clinicaltrials临床试验方案32Vulnerable PopulationsGroups tVulnerable PopulationsTo safe guard these groups,special requirements such as:Only parent can consent for minorConsents must be in subjects native lang.Prisoners:only some types of research allowedclinicaltrials临床试验方案33Vulnerable PopulationsTo safe Inclusion in Clinical TrialsNIH Revitalization Act of 1993:Guidelines that require inclusion of women&minorities in clinical studiesNew guidelines stipulate that:oWomen&minorities are to be included in all human subject researchoThey are to be included in Phase III trials to allow sufficient power to note differencesoCost cannot be a barrieroOutreach activities must take place to include&follow these groupsclinicaltrials临床试验方案34Inclusion in Clinical TrialsNIInclusion in Clinical TrialsHistorically women were excluded if of reproductive age(ages 18-45)Fear of harm to potential unborn childIn essence,excluded MAJORITY of womenNew guidelines eliminates this stipulationclinicaltrials临床试验方案35Inclusion in Clinical TrialsHiIssues in Clinical Trials:Use of Placebo TrialsOn international realm,1999“Declaration of Helsinki”revised to address use of placebos:Placebos not ethical in virtually all studies that involve diseases with PROVEN txRemain ethical in trials where no proven txRevisions due to controversy over use of placebos in attempting to find easy/cheap way to reduce HIV perinatal transmission 1998 study in Ivory Coast,Uganda,&Thailand:HIV+pregnant women given either placebo or shorter course of AZT clinicaltrials临床试验方案36Issues in Clinical Trials:UseParticipation in Clinical TrialsWhy Some Participate:Why Some Participate:Give back to societyExhausted all other txsHealth care servicesPayment&incentivesSupportOthers?Why Some Do Not?Why Some Do Not?Mistrust of studiesDo not want to be“guinea pig”Do not meet criteriaCannot give up time for study visitsBarriers:lang.,distanceclinicaltrials临床试验方案37Participation in Clinical TriaTaking Part in Research Studies:Questions to AskWhat is study about?What are the goals?Study sponsor?Participant input into protocols?Inclusion criteria?Benefits&risksIs there an incentive?How protected from harm?What is required:#study visit&what occurs?What happens after study is over?How results will be disseminated?clinicaltrials临床试验方案38Taking Part in Research StudieThe Impact of StudiesSome clinical trials have been critical to patient health&provision of health careFor instance:Protocol 076:HIV perinatal transmission1st trial of AZTVarious cancer treatmentsDevelopment of other HIV related medications like PIsclinicaltrials临床试验方案39The Impact of StudiesSome clinThe Impact of StudiesOther clinical trials have not been assuccessful for a variety of reasons:Medications did not work as in laboratoryLoss to Follow-Up of too many patientsHarmful substanceUnethical&poorly conducted study(Ex:Tuskegee Study&recent Gene Replacement Study)clinicaltrials临床试验方案40The Impact of StudiesOther cliConclusions&Take Home MessageClinical trials often yield important results that affect health and well beingMust follow guidelines&protocol Must ensure well-being of participantClinical trials are susceptible to human error either on part of investigator or patientResearch is soft scienceclinicaltrials临床试验方案41Conclusions&Take Home Messa