Understanding Clinical Trials

Developed by Sara Back, NP Bronx-Lebanon Hospital Center

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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
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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 ones 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.
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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
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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
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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

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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
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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.
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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 Helmonts proposal for a therapeutic trial of bloodletting for fevers [1628] Dr. Linds, a ship surgeon, trial of oranges & limes for scurvy [1747]

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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
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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
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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
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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
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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
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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
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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

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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.
Phase I 20 100 Phase II Up to
several 100

Length
Several months Several months2 yrs.

Purpose
Mainly Safety Short term safety; mainly effectiveness

% Drugs Successfully Tested

70% 33%

Phase III

100s several 1000

1-4 yrs.

Safety, dosage & effectiveness

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
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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
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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"
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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
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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
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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

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 NY/VI AETC

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
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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
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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
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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)
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Vulnerable Populations
To 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 allowed
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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

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
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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
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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?
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The Impact of Studies

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

Protocol 076: HIV perinatal transmission 1st trial of AZT Various cancer treatments Development of other HIV related medications like PIs
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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)
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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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