1、clinicaltrialsclinicaltrials临床试验临床试验方案方案Overview Purpose of Research Studies Classifications of Epidemiological Research Basic Research Terminology Features of Clinical Trials Design/Protocol Phases of a Study Ethics Protection of Participants Contributions of Clinical Trials Participating in a Tria
2、l Conclusion&Take Home Messageclinicaltrials临床试验方案2Overview to Research StudiesWhy Do Research Studies?To collect data on usual and unusual events,conditions,&population groups To test hypotheses formulated from observations and/or intuition Ultimately,to understand better ones world and make“sense
3、of it”clinicaltrials临床试验方案3Overview to Research Studies Various types of research studies Many classified as“Epidemiological Studies”Epidemiology often is defined as:clinicaltrials临床试验方案4Classifications of Research Studies:Three Main Types Groups are studied&contrasts made between groups The observe
4、d data collected are analyzed Also called Experimental Study the impact of a certain therapy Ultimately the investigator controls factor being studied Considered the“true”experimental study“Gold Standard”of clinical research Often a prospective study that compares the effect and value of an interven
5、tion against a control in human subjects clinicaltrials临床试验方案5Another Classification System Non-directed Data Capture Ex:Vital Statistics Directed Data Capture&Hypothesis Testing Ex:Cohort Studies,Case Control Studies Clinical Trials Ex:Investigation of Treatment/Condition Ex:Drug Trialsclinicaltria
6、ls临床试验方案6The Different Study Designs Case-control Cohort Case Reports Case Series Outcomes Based:Survey Research:Quality of LifeQuestionnairesDecision analysis Polls Economic AnalysisSurveys Meta Analyses Survival Analysis Randomized Clinical Trialclinicaltrials临床试验方案7Basic Research Terminology Refe
7、rs to time of data collection Refers to time of data collection Persons w/disease&those w/out are compared Persons w/and/or w/out disease are followed over timeclinicaltrials临床试验方案8Terminology(Cont.)Presence or absence of exposure to possible risk factor measured at one point in time.Prevalence obta
8、ined.The#of new cases and existing cases during specified time period.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9Historical MinuteFirst“Clinical Trials”Clinical Trials have a long history even if not acknowledged as Clinical
9、 trials Formal record of clinical trials dates back to the time of the“Trialists”:Dr.Van Helmonts proposal for a therapeutic trial of bloodletting for fevers 1628 Dr.Linds,a ship surgeon,trial of oranges&limes for scurvy 1747 clinicaltrials临床试验方案10Historical MinuteFirst“Clinical Trials”1909:Paul Ehr
10、lich-Arsphenamine 1929:Alexander Fleming-Penicillin 1935:Gerhard Domagk-Sulfonamide 1944:Schatz/Bugie/Waksman Streptomycin By 1950,the British Medical Res.Council developed a systematic methodology for studying&evaluating therapeutic interventionsclinicaltrials临床试验方案11Core Components of Clinical Tri
11、als Involve human subjects Move forward in time Most have a comparison CONTROL group Must have method to measure intervention Focus on unknowns:effect of medication Must be done before medication is part of standard of care Conducted early in the development of therapiesclinicaltrials临床试验方案12Core Co
12、mponents of Clinical Trials Must review existing scientific data&build on that knowledge Test a certain hypothesis Study protocol must be built on soundðical science Control for any potential biases Most study medications,procedures,and/or other interventions clinicaltrials临床试验方案13The Possible Wo
13、rld of Clinical Trial Designs Randomized/blinded trial Randomized/double blinded trial Non-randomized concurrent controlled trial Placebo trial Historical controlled trial Crossover Trial Withdrawal trialclinicaltrials临床试验方案14Simplified Schemes used to assign participant to one groupEx:Every 3 gets
14、higher dose All with Hep.C=cases;others=controls Study design-instructions Participants do not know if in experimental or control group Participants AND staff do not know group assignment Inactive pill w/no therapeutic valueclinicaltrials临床试验方案15Components of Clinical Trial Protocols Investigating t
15、wo or more conditions so have two(+)groups Ex:drug vs.placebo;medicine vs.surgery;low dose vs.high dose Specific inclusion/exclusion criteria Sample size&power calculations Plan re:potential biases Plan re:handling of attrition/loss to follow up clinicaltrials临床试验方案16Study Participant Recruitment Id
16、entify eligible participants Explain study Provide informed consent Reassess eligibility Assign to one groupParticipants should be told:May have side effects(adverse effects)Time commitment Benefits&risks May withdraw at any time Enrollment 100%voluntary clinicaltrials临床试验方案17Phases of Clinical Tria
17、ls Most 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 Trials Small group 20-80 for 1st time to evaluate safety,determine safe dosage range&identify SE Rx/tx given to larger
18、group 100-300 to confirm effectiveness,monitor SE,&further evaluate safetyclinicaltrials临床试验方案19Phases of Clinical Trials(cont.)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 safely D
19、one 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20Summary of Phases I-III20 100Several monthsMainly Safety70%Up to several 100Several months-2 yrs.Short term safety;mainly effectiveness33%
20、100s several 10001-4 yrs.Safety,dosage&effectiveness25-30%clinicaltrials临床试验方案21Ethics of Clinical Trials:Protection of Participants3 ethical principles guide clinical research:Treatment of person as autonomous Issue re:potential conflict between good of society vs.individual Treatment of all fairly
21、&all equally share benefits&risksclinicaltrials临床试验方案22Ethical Norms of Clinical TrialsSound study designs take into account:Randomization or sharing of risks Proper use of placebo Processes to monitor safety of rx/tx Competent investigators Informed consent Equitable selection of participants Compe
22、nsation for study related injuriesclinicaltrials临床试验方案23Human Subjects Protection Review research to ensure that potential benefits outweigh risks Develop and issue written procedures Review research for risk/benefit analysis&proper protection of subjects Issue written notice of approval/disapproval
23、 to the Investigator Review and respond to proposed protocol changes submitted by the Investigatorclinicaltrials临床试验方案25Human Subjects Protection Review reports of deaths,and serious and unexpected adverse events received from the Investigator Conduct periodic continuing review of the study,study ri
24、sks,selection of subjects,privacy of subjects,confidentiality of data,and the consent processclinicaltrials临床试验方案26Historical Minute:Origin of IRBs&Human Subject Code Attention to protecting participants began after WWII w/the Nuremberg Trials(1947)Out of those trials,key points were codifiedclinica
25、ltrials临床试验方案27Historical 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 w
26、ill 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:Origin of IRBs&Human Subject Codes Since 1947,additional subject protect
27、ion 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
28、临床试验方案29Informed Consent:A Part of Human Subject ProtectionObjectives of Informed ConsentTo Ensure:Voluntariness Comprehension InformationTo Demonstrate That:Person freely gave consent to participate Consent given by a competent person Person has been given all information Person knows this is resea
29、rch not treatmentclinicaltrials临床试验方案30Components of Informed Consent Must Include the Following Information:Why research being done?What researchers want to accomplish What will be done and for how long Risks&benefits of trial Other treatments available Can withdraw from trial whenever desire Compe
30、nsation for unexpected injuriesclinicaltrials临床试验方案31Vulnerable PopulationsGroups thought not to have autonomy to give informed consent:children mentally impaired,individuals with dementia PrisonersWho may be unduly influenced to participate:students subordinates pregnant women(actually,the fetuses)
31、patients(care-giver vs.researcher)clinicaltrials临床试验方案32Vulnerable PopulationsTo safe guard these groups,special requirements such as:Only parent can consent for minor Consents must be in subjects native lang.Prisoners:only some types of research allowedclinicaltrials临床试验方案33Inclusion in Clinical Tr
32、ials Guidelines that require inclusion of women&minorities in clinical studies New 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
33、activities must take place to include&follow these groupsclinicaltrials临床试验方案34Inclusion in Clinical Trials Historically women were excluded if of reproductive age(ages 18-45)Fear of harm to potential unborn child In essence,excluded MAJORITY of women New guidelines eliminates this stipulationclinic
34、altrials临床试验方案35Issues 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 tx Remain ethical in trials where no proven tx Revisions due to contro
35、versy 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 AZTclinicaltrials临床试验方案36Participation in Clinical Trials Give back to society Exhausted all ot
36、her txs Health care services Payment&incentives Support Others?Mistrust of studies Do not want to be“guinea pig”Do not meet criteria Cannot give up time for study visits Barriers:lang.,distanceclinicaltrials临床试验方案37Taking Part in Research Studies:Questions to Ask What is study about?What are the goa
37、ls?Study sponsor?Participant input into protocols?Inclusion criteria?Benefits&risks Is 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38The Impact of Studies Some clinical tria
38、ls have been critical to patient health&provision of health care For 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 StudiesOther clinical trials have not been assuccessf
39、ul for a variety of reasons:Medications did not work as in laboratory Loss to Follow-Up of too many patients Harmful substance Unethical&poorly conducted study(Ex:Tuskegee Study&recent Gene Replacement Study)clinicaltrials临床试验方案40Conclusions&Take Home Message Clinical trials often yield important results that affect health and well being Must follow guidelines&protocol Must ensure well-being of participant Clinical trials are susceptible to human error either on part of investigator or patient Research is soft scienceclinicaltrials临床试验方案41
