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Understanding Clinical Trials

Understanding Clinical Trials. Developed by Sara Back, NP Bronx-Lebanon Hospital Center. Overview. Purpose of Research Studies Classifications of Epidemiological Research Basic Research Terminology Features of Clinical Trials Design/Protocol Phases of a Study Ethics

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Understanding Clinical Trials

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  1. Understanding Clinical Trials Developed by Sara Back, NP Bronx-Lebanon Hospital Center NY/VI AETC

  2. Overview • Purpose ofResearch 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 Message NY/VI AETC

  3. Overview to Research Studies Why 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 one’s world and make “sense of it” NY/VI AETC

  4. Overview to Research Studies • Various 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. NY/VI AETC

  5. Observational Studies: Groups are studied & contrasts made between groups The observed data collected are analyzed Analytic Studies: Also called Experimental Study the impact of a certain therapy Ultimately the investigator controls factor being studied Clinical Trial: 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 in human subjects Classifications of Research Studies: Three Main Types NY/VI AETC

  6. Another 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 NY/VI AETC

  7. The Different Study Designs • Case-control • Cohort • Case Reports • Case Series • Outcomes Based: • Survey Research: Quality of Life Questionnaires Decision analysis Polls Economic Analysis Surveys • Meta Analyses • Survival Analysis • Randomized Clinical Trial NY/VI AETC

  8. Basic Research Terminology • Retrospective:Refers to time of data collection • Prospective:Refers to time of data collection • Case Control Study:Persons w/ disease & those w/out are compared • Cohort Study:Persons w/ and/or w/out disease are followed over time NY/VI AETC

  9. Terminology (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. NY/VI AETC

  10. Historical MinuteFirst “Clinical Trials” • Clinical Trials have a long history – even if not acknowledged as Clinical trials • Formal record of clinical trials dates back to the time of the “Trialists”: • Dr. Van Helmont’s proposal for a therapeutic trial of bloodletting for fevers [1628] • Dr. Lind’s, a ship surgeon, trial of oranges & limes for scurvy [1747] NY/VI AETC

  11. Historical MinuteFirst “Clinical Trials” Historical Highlights of Drug Trials • 1909:Paul Ehrlich - 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 NY/VI AETC

  12. Core Components of Clinical 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 NY/VI AETC

  13. Core Components 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 NY/VI AETC

  14. The Possible 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 NY/VI AETC

  15. Randomized: Schemes used to assign participant to one group Ex: Every 3 gets higher dose Nonrandomized: All with Hep. C = cases; others = controls Protocol: Study design - instructions Blinded: Participants do not know if in experimental or control group Double Blinded: Participants AND staff do not know group assignment Placebo: Inactive pill w/ no therapeutic value Simplified NY/VI AETC

  16. Components of Clinical Trial Protocols • Investigating 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 NY/VI AETC

  17. Identify eligible participants Explain study Provide informed consent Reassess eligibility Assign to one group Participants should be told: May have side effects (adverse effects) Time commitment Benefits & risks May withdraw at any time Enrollment 100% voluntary Study Participant Recruitment NY/VI AETC

  18. Phases 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 NY/VI AETC

  19. Phases of Clinical Trials • Phase I: Small group [20-80] for 1st time to evaluate safety, determine safe dosage range & identify SE • Phase II:Rx/tx given to larger group [100-300] to confirm effectiveness, monitor SE, & further evaluate safety NY/VI AETC

  20. Phases of Clinical Trials (cont.) • 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 safely • 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. NY/VI AETC

  21. Summary of Phases I-III NY/VI AETC

  22. Ethics of Clinical Trials: Protection of Participants 3 ethical principles guide clinical research: • Respect for Persons: Treatment of person as autonomous • Beneficence: Issue re: potential conflict between good of society vs. individual • Justice: Treatment of all fairly & all equally share benefits & risks NY/VI AETC

  23. Ethical Norms of Clinical Trials Sound 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 • Compensation for study related injuries NY/VI AETC

  24. Ethical Issues: Protection of Human Subjects • Rely on integrity of Investigator but outside groups also have oversight • Participants’ rights protected by Institutional Review Boards [IRBs] • An 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 subjects" NY/VI AETC

  25. Human Subjects’ Protection IRB responsible for such tasks: • 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 to the Investigator • Review and respond to proposed protocol changes submitted by the Investigator NY/VI AETC

  26. Human Subjects’ Protection • IRB Responsibilities (continued): • 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 NY/VI AETC

  27. Historical 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 codified NY/VI AETC

  28. Voluntary informed consent Experiment must be for the good of society, & results not obtainable by other means Experiment should be based upon prior animal studies Physical & mental suffering & injury should be avoided No expectation that death/disabling injury will occur from the experiment Risk vs. benefit Protect subjects against injury, disability, or death Only scientifically qualified persons to be involved Subject can terminate her/his involvement Historical Minute:10 Key Points NY/VI AETC

  29. Historical 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 additional study requirements related to: informed consent training req. adverse events conflict of interest civil monetary penalties improved monitoring of Phase I & II trials NY/VI AETC

  30. Informed Consent:A Part of Human Subject Protection Objectives of Informed Consent To Ensure: • Voluntariness • Comprehension • Information To 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 NY/VI AETC

  31. Components 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 • Compensation for unexpected injuries NY/VI AETC

  32. Vulnerable Populations Groups thought not to have autonomy to give informed consent: • children • mentally impaired, individuals with dementia • Prisoners OR Who may be unduly influenced to participate: • students • subordinates • pregnant women (actually, the fetuses) • patients (care-giver vs. researcher) NY/VI AETC

  33. Vulnerable Populations To safe guard these groups, special requirements such as: • Only parent can consent for minor • Consents must be in subject’s native lang. • Prisoners: only some types of research allowed NY/VI AETC

  34. Inclusion in Clinical Trials • NIH Revitalization Act of 1993: Guidelines that require inclusion of women & minorities in clinical studies • New guidelines stipulate that: • Women & minorities are to be included in all human subject research • They are to be included in Phase III trials to allow sufficient power to note differences • Cost cannot be a barrier • Outreach activities must take place to include & follow these groups NY/VI AETC

  35. Inclusion 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 stipulation NY/VI AETC

  36. Issues in Clinical Trials:Use of Placebo Trials On 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 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 NY/VI AETC

  37. Why Some Participate: Give back to society Exhausted all other txs Health care services Payment & incentives Support Others?? Why Some Do Not? Mistrust of studies Do not want to be “guinea pig” Do not meet criteria Cannot give up time for study visits Barriers: lang., distance Participation in Clinical Trials NY/VI AETC

  38. What is study about? What are the goals? 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? Taking Part in Research Studies:Questions to Ask NY/VI AETC

  39. The Impact of Studies • Some clinical trials have been critical to patient health & provision of health care • For instance: • Protocol 076:  HIV perinatal transmission • 1st trial of AZT • Various cancer treatments • Development of other HIV related medications like PIs NY/VI AETC

  40. The Impact of Studies Other clinical trials have not been as successful 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) NY/VI AETC

  41. Conclusions & 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 science NY/VI AETC

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