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Understanding Clinical Trials:

Understanding Clinical Trials Presented by Yashraj Yadav CRC

Overview:

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 Trial Conclusion & Take Home Message March 26, 2011 yash t yadav 2

Overview to Research Studies:

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” March 26, 2011 yash t yadav 3

Overview to Research Studies:

Overview to Research Studies Various types of research studies Many classified as “Epidemiological Studies” Epidemiology often is defined as: March 26, 2011 yash t yadav The study of the distribution of a disease or condition in a population and the factors that influence that distribution. 4

Classifications of Research Studies: Three Main Types:

Classifications of Research Studies: Three Main Types 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 March 26, 2011 yash t yadav 5

Another Classification System :

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 March 26, 2011 yash t yadav 6

The Different Study Designs:

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 March 26, 2011 yash t yadav 7

Basic Research Terminology:

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 March 26, 2011 yash t yadav 8

Terminology (Cont.):

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. March 26, 2011 yash t yadav 9

Historical Minute First “Clinical Trials”:

Historical Minute First “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] March 26, 2011 yash t yadav

Historical Minute First “Clinical Trials”:

Historical Minute First “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 March 26, 2011 yash t yadav 11

Core Components of Clinical Trials:

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 March 26, 2011 yash t yadav 12

Core Components of Clinical Trials:

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 March 26, 2011 yash t yadav 13

The Possible World of Clinical Trial Designs:

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 March 26, 2011 yash t yadav 14

Simplified:

Simplified 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 March 26, 2011 yash t yadav 15

Components of Clinical Trial Protocols :

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 March 26, 2011 yash t yadav 16

Study Participant Recruitment:

Study Participant Recruitment 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 March 26, 2011 yash t yadav 17

Phases of Clinical Trials:

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 March 26, 2011 yash t yadav 18

Phases of Clinical Trials:

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 March 26, 2011 yash t yadav 19

Phases of Clinical Trials (cont.):

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. March 26, 2011 yash t yadav 20

Summary of Phases I-III:

Summary of Phases I-III # Subs. Length Purpose % Drugs Successfully Tested Phase I 20 – 100 Several months Mainly Safety 70% Phase II Up to several 100 Several months- 2 yrs. Short term safety; mainly effectiveness 33% Phase III 100s – several 1000 1-4 yrs. Safety, dosage & effectiveness 25-30% March 26, 2011 yash t yadav

Ethics of Clinical Trials: Protection of Participants:

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 March 26, 2011 yash t yadav 22

Ethical Norms of Clinical Trials:

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 March 26, 2011 yash t yadav 23

Ethical Issues: Protection of Human Subjects:

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" March 26, 2011 yash t yadav 24

Human Subjects’ Protection:

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 March 26, 2011 yash t yadav 25

Human Subjects’ Protection:

Human Subjects’ Protection 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 March 26, 2011 yash t yadav IRB Responsibilities (continued): 26

Historical Minute: Origin of IRBs & Human Subject Code:

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 March 26, 2011 yash t yadav

Historical Minute: 10 Key Points:

Historical Minute: 10 Key Points 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 March 26, 2011 yash t yadav 28

Historical Minute: Origin of IRBs & Human Subject Codes:

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 March 26, 2011 yash t yadav 29

Informed Consent: A Part of Human Subject Protection:

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 March 26, 2011 yash t yadav

Components of Informed Consent:

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 March 26, 2011 yash t yadav 31

Vulnerable Populations:

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) March 26, 2011 yash t yadav 32

Vulnerable Populations:

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 March 26, 2011 yash t yadav 33

Inclusion in Clinical Trials:

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 March 26, 2011 yash t yadav 34

Inclusion in Clinical Trials:

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 March 26, 2011 yash t yadav 35

Issues in Clinical Trials: Use of Placebo Trials:

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 March 26, 2011 yash t yadav 36

Participation in Clinical Trials:

Participation in Clinical Trials 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 March 26, 2011 yash t yadav 37

Taking Part in Research Studies: Questions to Ask:

Taking Part in Research Studies: Questions to Ask 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? March 26, 2011 yash t yadav 38

The Impact of Studies:

The Impact of Studies Some clinical trials have been critical to patient health & provision of health care For instance: Protocol 076:  HIV perinatal transmission 1 st trial of AZT Various cancer treatments Development of other HIV related medications like PIs March 26, 2011 yash t yadav 39

The Impact of Studies:

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) March 26, 2011 yash t yadav 40

Conclusions & Take Home Message:

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 March 26, 2011 yash t yadav 41

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