Transcript Clinical Trials

Understanding
Clinical Trials
Developed by Sara Back, NP
Bronx-Lebanon Hospital Center
NY/VI AETC
Overview
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Purpose of Research Studies
Classifications of Epidemiological Research
Basic Research Terminology
Features of Clinical Trials
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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 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.
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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 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]
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Historical Minute
First “Clinical Trials”
Historical Highlights of Drug Trials
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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
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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
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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
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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
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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
Length
Purpose
% Drugs
Successfully
Tested
Phase I 20 – 100
Several
months
Mainly Safety
70%
Phase II Up to
Several
months2 yrs.
1-4 yrs.
Short term
safety; mainly
effectiveness
Safety, dosage
& effectiveness
33%
# Subs.
Phase
III
several
100
100s –
several
1000
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]
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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
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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
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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
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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
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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 subject’s 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:
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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
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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:
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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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