clinicaltrials临床试验方案PPT课件

1、NY/VI AETCOverview 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 Trial Conclusion & Take Home Messa

2、ge第1页/共41页NY/VI AETCOverview 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 of it”第2页/共41页NY/VI AETCO

3、verview to Research Studies Various types of research studies Many classified as “Epidemiological Studies”Epidemiology often is defined as:第3页/共41页NY/VI AETCClassifications of Research Studies: Three Main Types Groups are studied & contrasts made between groups The observed data collected are analyz

4、ed 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 intervention against a control

5、in human subjects 第4页/共41页NY/VI AETCAnother 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 Trials第5页/共41页NY/VI AETCThe Different

6、 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 Trial第6页/共41页NY/VI AETCBasic Research Terminology Refers to time of data coll

7、ection Refers to time of data collection Persons w/ disease & those w/out are compared Persons w/ and/or w/out disease are followed over time第7页/共41页NY/VI AETCTerminology (Cont.) Presence or absence of exposure to possible risk factor measured at one point in time. Prevalence obtained. The # of new

8、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.第8页/共41页NY/VI AETCHistorical MinuteFirst “Clinical Trials” Clinical Trials have a long history even if not acknowledged as Clinical trials Formal

9、 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 第9页/共41页NY/VI AETCHistorical MinuteFirst “Clinical Trials” 1909: Paul Ehrlich -

10、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 interventions第10页/共41页NY/VI AETCCore Components of Clinical

11、Trials 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 therapies第11页/共41页NY/VI AETCCore C

12、omponents of Clinical Trials Must review existing scientific data & build on that knowledge Test a certain hypothesis Study protocol must be built on sound & ethical science Control for any potential biases Most study medications, procedures, and/or other interventions 第12页/共41页NY/VI AETCThe Possibl

13、e World of Clinical Trial Designs Randomized/blinded trial Randomized/double blinded trial Non-randomized concurrent controlled trial Placebo trial Historical controlled trial Crossover Trial Withdrawal trial第13页/共41页NY/VI AETCSimplified Schemes used to assign participant to one groupoEx: Every 3 ge

14、ts 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 value第14页/共41页NY/VI AETCComponents of Clinical Trial Protocols Invest

15、igating two 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 第15页/共41页NY/VI AETCStudy Participa

16、nt Recruitment Identify 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 第16页/共41页NY/VI AETCPha

17、ses of Clinical Trials 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 phases第17页/共41页NY/VI AETCPhases of Clinical Trials Small group 20-80 for 1st time to evaluate safety, determine safe dosage range & identify

18、SE Rx/tx given to larger group 100-300 to confirm effectiveness, monitor SE, & further evaluate safety第18页/共41页NY/VI AETCPhases 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 wi

19、ll allow it to be used safely 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.第19页/共41页NY/VI AETCSummary of Phases I-III20 100Several monthsMainly Safety70%Up to several 100Several months- 2 yrs.Short te

20、rm safety; mainly effectiveness33%100s 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: Treatment of person as autonomous Issue re: potential conflict between good of society

21、vs. individual 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: Randomization or sharing of risks Proper use of placebo Processes to monitor safety of rx/tx Competent investigators Informed consent E

22、quitable selection of participants Compensation for study related injuries第22页/共41页NY/VI AETCEthical Issues: Protection of Human Subjects Rely on integrity of Investigator but outside groups also have oversight Participants rights protected by Institutional Review Boards IRBsoAn IRB is defined as: a

23、ny 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 subjects第23页/共41页NY/VI AETCHuman Subjects Protection Review research to ensure that potential benefits outweigh risk

24、s Develop and issue written procedures Review research for risk/benefit analysis & proper protection of subjects Issue written notice of approval/disapproval to the Investigator Review and respond to proposed protocol changes submitted by the Investigator第24页/共41页NY/VI AETCHuman Subjects Protection

25、Review reports of deaths, and serious and unexpected adverse events received from the Investigator Conduct periodic continuing review of the study, study risks, selection of subjects, privacy of subjects, confidentiality of data, and the consent process第25页/共41页NY/VI AETCHistorical Minute:Origin of

26、IRBs & Human Subject Code Attention to protecting participants began after WWII w/ the Nuremberg Trials (1947) 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

27、 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 person

28、s to be involvedSubject can terminate her/his involvement第27页/共41页NY/VI AETCHistorical Minute: Origin of IRBs & Human Subject Codes Since 1947, additional subject protection requirements developed & implemented Latest additions: Year 2000 - President Clinton & DHHS Secretary Shalala announced additi

29、onal study requirements related to: informed consenttraining req. adverse eventsconflict of interest civil monetary penaltiesimproved 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: Voluntariness Comprehe

30、nsion 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 research not treatment第29页/共41页NY/VI AETCComponents of Informed Consent Must Include the Following Information: Why research

31、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 Compensation for unexpected injuries第30页/共41页NY/VI AETCVulnerable PopulationsGroups thought not to have autonomy to give inf

32、ormed consent: children mentally impaired, individuals with dementia PrisonersWho may be unduly influenced to participate: students subordinates pregnant women (actually, the fetuses) patients (care-giver vs. researcher)第31页/共41页NY/VI AETCVulnerable PopulationsTo safe guard these groups, special req

33、uirements such as: Only parent can consent for minor Consents must be in subjects native lang. Prisoners: only some types of research allowed第32页/共41页NY/VI AETCInclusion in Clinical Trials Guidelines that require inclusion of women & minorities in clinical studies New guidelines stipulate that:oWome

34、n & 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 groups第33页/共41页NY/VI AETCInclusion in Clinical Trials Histo

35、rically 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 stipulation第34页/共41页NY/VI AETCIssues in Clinical Trials:Use of Placebo TrialsOn international realm, 1999 “Declaration of Helsi

36、nki” 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 controversy over use of placebos in attempting to find easy/cheap way to reduce HIV perinatal transmission 1998 stu

37、dy in Ivory Coast, Uganda, & Thailand: HIV+ pregnant women given either placebo or shorter course of AZT第35页/共41页NY/VI AETCParticipation in Clinical Trials Give back to society Exhausted all other 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., distance第36页/共41页NY/VI AETCTaking Part in Resea