clinicaltrials临床试验方案.pptx

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1、NY/VI AETCOverview 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 Message第1页/共

2、41页NY/VI AETCOverview 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”第2页/共41页NY/VI AETCOverview to Rese

3、arch 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.第3页/共41页NY/VI AETCClassifications of Research Studies:Thr

4、ee 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 studied

5、Clinical 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 第4页/共41页NY/VI AETCAnother Classification SystemNon-directed Data Capture Ex:Vital

6、 StatisticsDirected Data Capture&Hypothesis Testing Ex:Cohort Studies,Case Control StudiesClinical Trials Ex:Investigation of Treatment/Condition Ex:Drug Trials第5页/共41页NY/VI AETCThe Different Study DesignsCase-control CohortCase Reports Case SeriesOutcomes Based:Survey Research:Quality of LifeQuesti

7、onnairesDecision analysis Polls Economic AnalysisSurveysMeta AnalysesSurvival AnalysisRandomized Clinical Trial第6页/共41页NY/VI AETCBasic Research Terminology Retrospective:Retrospective:Refers to time of data collection Prospective:Prospective:Refers to time of data collection Case Control Study:Case

8、Control Study:Persons w/disease&those w/out are compared Cohort Study:Cohort Study:Persons w/and/or w/out disease are followed over time第7页/共41页NY/VI AETCTerminology(Cont.)Cross-sectional Study:Cross-sectional Study:Presence or absence of exposure to possible risk factor measured at one point in tim

9、e.Prevalence obtained.Prevalence:Prevalence:The#of new cases and existing cases during specified time period.Incidence:Incidence:The#of NEW cases per unit of a population at risk for disease occurring during stated time period.第8页/共41页NY/VI AETCHistorical MinuteFirst“Clinical Trials”Clinical Trials

10、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 第9页/共41页NY/VI AETCHi

11、storical MinuteFirst“Clinical Trials”Historical Highlights of Drug TrialsHistorical 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 systema

12、tic methodology for studying&evaluating therapeutic interventions第10页/共41页NY/VI AETCCore 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 medica

13、tion is part of standard of careConducted early in the development of therapies第11页/共41页NY/VI AETCCore 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 bias

14、esMost study medications,procedures,and/or other interventions 第12页/共41页NY/VI AETCThe Possible World of Clinical Trial DesignsRandomized/blinded trialRandomized/double blinded trialNon-randomized concurrent controlled trialPlacebo trialHistorical controlled trialCrossover TrialWithdrawal trial第13页/共

15、41页NY/VI AETCSimplified Randomized:Randomized:Schemes used to assign participant to one groupoEx:Every 3 gets higher dose Nonrandomized:Nonrandomized:All with Hep.C=cases;others=controls Protocol:Protocol:Study design-instructions Blinded:Blinded:Participants do not know if in experimental or contro

16、l group Double Blinded:Double Blinded:Participants AND staff do not know group assignment Placebo:Placebo:Inactive pill w/no therapeutic value第14页/共41页NY/VI AETCComponents of Clinical Trial Protocols Investigating two or more conditions so have two(+)groupsEx:drug vs.placebo;medicine vs.surgery;low

17、dose vs.high doseSpecific inclusion/exclusion criteriaSample size&power calculationsPlan re:potential biasesPlan re:handling of attrition/loss to follow up 第15页/共41页NY/VI AETCStudy Participant RecruitmentIdentify eligible participantsExplain studyProvide informed consentReassess eligibilityAssign to

18、 one groupParticipants should be told:May have side effects(adverse effects)Time commitmentBenefits&risksMay withdraw at any timeEnrollment 100%voluntary 第16页/共41页NY/VI AETCPhases of Clinical TrialsMost trials that involve new drugs go through a series of steps:#1:Experiments in the laboratory#2:Onc

19、e deemed safe,go through 1-4 phases第17页/共41页NY/VI AETCPhases of Clinical Trials Phase I:Phase I:Small group 20-80 for 1st time to evaluate safety,determine safe dosage range&identify SE Phase II:Phase II:Rx/tx given to larger group 100-300 to confirm effectiveness,monitor SE,&further evaluate safety

20、第18页/共41页NY/VI AETCPhases 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-studie

21、s continue to test rx/tx to collect data about effects in various populations&SE from long term use.第19页/共41页NY/VI AETCSummary of Phases I-III#Subs.#Subs.LengthLengthPurposePurpose%Drugs%Drugs Successfully Successfully TestedTestedPhase IPhase I20 100Several monthsMainly Safety70%Phase IIPhase IIUp

22、to several 100Several months-2 yrs.Short term safety;mainly effectiveness33%Phase Phase IIIIII100s several 10001-4 yrs.Safety,dosage&effectiveness25-30%第20页/共41页NY/VI AETCEthics of Clinical Trials:Protection of Participants3 ethical principles guide clinical research:Respect for Persons:Respect for

23、Persons:Treatment of person as autonomous Beneficence:Beneficence:Issue re:potential conflict between good of society vs.individual Justice:Justice:Treatment of all fairly&all equally share benefits&risks第21页/共41页NY/VI AETCEthical Norms of Clinical TrialsSound study designs take into account:Randomi

24、zation or sharing of risksProper use of placebo Processes to monitor safety of rx/txCompetent investigatorsInformed consentEquitable selection of participantsCompensation for study related injuries第22页/共41页NY/VI AETCEthical Issues:Protection of Human SubjectsRely on integrity of Investigator but out

25、side groups also have oversightParticipants rights protected by Institutional Review Boards IRBsoAn IRB is defined as:any board,committee or other group formally designated by an institution to review,to approve the initiation of,and to conduct periodic review of biomedical research involving human

26、subjects第23页/共41页NY/VI AETCHuman 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

27、notice of approval/disapproval to the InvestigatorReview and respond to proposed protocol changes submitted by the Investigator第24页/共41页NY/VI AETCHuman Subjects ProtectionReview reports of deaths,and serious and unexpected adverse events received from the InvestigatorConduct periodic continuing revi

28、ew of the study,study risks,selection of subjects,privacy of subjects,confidentiality of data,and the consent processIRB Responsibilities(continued):第25页/共41页NY/VI AETCHistorical Minute:Origin of IRBs&Human Subject CodeAttention to protecting participants began after WWII w/the Nuremberg Trials(1947

29、)Out of those trials,key points were codified第26页/共41页NY/VI AETCHistorical 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 av

30、oidedNo 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 involvement第27页/共41页NY/VI AETCHistorical Minute:Origin of IRBs&Human Subje

31、ct 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

32、monitoring of Phase I&II trials第28页/共41页NY/VI AETCInformed 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

33、 information Person knows this is research not treatment第29页/共41页NY/VI AETCComponents 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 f

34、rom trial whenever desireCompensation for unexpected injuries第30页/共41页NY/VI AETCVulnerable PopulationsGroups thought not to have autonomy to give informed consent:childrenmentally impaired,individuals with dementiaPrisonersOR OR Who may be unduly influenced to participate:studentssubordinatespregnan

35、t women(actually,the fetuses)patients(care-giver vs.researcher)第31页/共41页NY/VI AETCVulnerable 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 allowed第32页/共41页NY/VI AETCIn

36、clusion in Clinical Trials NIH Revitalization Act of 1993:NIH 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 tria

37、ls to allow sufficient power to note differencesoCost cannot be a barrieroOutreach activities must take place to include&follow these groups第33页/共41页NY/VI AETCInclusion in Clinical TrialsHistorically women were excluded if of reproductive age(ages 18-45)Fear of harm to potential unborn childIn essen

38、ce,excluded MAJORITY of womenNew guidelines eliminates this stipulation第34页/共41页NY/VI AETCIssues 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 PRO

39、VEN 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 第35页/共41页NY/VI AETC

40、Participation 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 v

41、isitsBarriers:lang.,distance第36页/共41页NY/VI AETCTaking 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 occur

42、s?What happens after study is over?How results will be disseminated?第37页/共41页NY/VI AETCThe Impact of StudiesSome clinical trials have been critical to patient health&provision of health careFor instance:oProtocol 076:HIV perinatal transmissiono1st trial of AZToVarious cancer treatmentsoDevelopment o

43、f other HIV related medications like PIs第38页/共41页NY/VI AETCThe 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

44、&recent Gene Replacement Study)第39页/共41页NY/VI AETCConclusions&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 science第40页/共41页NY/VI AETC感谢您的观看！第41页/共41页