Understanding Clinical Trials

Understanding Clinical Trials

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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 NY/VI AETC

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”

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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

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 NY/VI AETC

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

The Different Study Designs • Case-control • Cohort • Case Reports • Case Series • Outcomes Based: • Survey Research: Quality of Life Decision analysis Economic Analysis

Questionnaires Polls Surveys

• Meta Analyses • Survival Analysis • Randomized Clinical Trial NY/VI AETC

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

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

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] NY/VI AETC

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 NY/VI AETC

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

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

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

Simplified • Randomized: Schemes used to assign participant to one group o

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 NY/VI AETC

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

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Specific inclusion/exclusion criteria Sample size & power calculations Plan re: potential biases Plan re: handling of attrition/loss to follow up NY/VI AETC

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 NY/VI AETC

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

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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 [100300] to confirm effectiveness, monitor SE, & further evaluate safety

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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.

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Summary of Phases I-III # Subs. Length Purpose Phase I 20 – 100 Phase II Up to Phase III

several 100 100s – several 1000

Several months Several months2 yrs. 1-4 yrs.

% Drugs Successfully Tested

Mainly Safety

70%

Short term safety; mainly effectiveness Safety, dosage & effectiveness

33%

25-30%

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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

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

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] o

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

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

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

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

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Historical Minute: 10 Key Points •

Voluntary informed consent

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Experiment must be for the good of society, & results not obtainable by other means

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Experiment should be based upon prior animal studies

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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 NY/VI AETC

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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

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

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

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

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

Inclusion in Clinical Trials • NIH Revitalization Act of 1993: Guidelines that require inclusion of women & minorities in clinical studies • New guidelines stipulate that: o o o o

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

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

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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

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

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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? NY/VI AETC

The Impact of Studies • Some clinical trials have been critical to patient health & provision of health care • For instance: o o o o

Protocol 076: ↓ HIV perinatal transmission 1st trial of AZT Various cancer treatments Development of other HIV related medications like PIs NY/VI AETC

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

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

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