NY/VI AETC

Understanding
Clinical Trials
Developed by Sara Back, NP
Bronx-Lebanon Hospital Center
NY/VI AETC
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 ones
world and make sense of it
NY/VI AETC
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: I nvestigation 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 Questionnaires
Decision analysis Polls
Economic Analysis 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
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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.

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 Helmonts proposal for a therapeutic
trial of bloodletting for fevers [1628]
Dr. Linds, 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
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

NY/VI AETC
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
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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.

NY/VI AETC
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%
NY/VI AETC
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"

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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

NY/VI AETC
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

IRB Responsibilities (continued):
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

NY/VI AETC
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

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 subjects 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 Women & minorities are to be included in all
human subject research
o They are to be included in Phase III trials to
allow sufficient power to note differences
o Cost cannot be a barrier
o 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
NY/VI AETC
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

NY/VI AETC
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 Protocol 076: HIV perinatal transmission
o 1
st
trial of AZT
o Various cancer treatments
o 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