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
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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 Questionnaires
Decision analysis Polls
Economic Analysis 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
• 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: • Blinded: Participants
Schemes used to do not know if in
assign participant to experimental or control
one group group
o Ex: Every 3 gets higher
dose • Double Blinded:
• Nonrandomized: All Participants AND staff
with Hep. C = cases; do not know group
others = controls assignment
• Protocol: Study • Placebo: Inactive pill
design - instructions 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 should be told:
participants • May have side effects
• Explain study (adverse effects)
• Provide informed • Time commitment
consent • Benefits & risks
• Reassess eligibility • May withdraw at any time
• Assign to one group • 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 [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.

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

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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 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:
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
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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: Why Some Do Not?
• Give back to society • Mistrust of studies
• Exhausted all other txs • Do not want to be
• Health care services “guinea pig”
• Payment & incentives • Do not meet criteria
• Support • Cannot give up time for
• Others?? study visits
• Barriers: lang., distance

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 Taking Part in Research Studies:
Questions to Ask
• What is study about? • Is there an incentive?
• What are the goals? • How protected from
• Study sponsor? harm?
• Participant input into • What is required: # study
protocols? visit & what occurs?
• Inclusion criteria? • What happens after study
• Benefits & risks 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 Protocol 076: ↓ HIV perinatal transmission
o 1st trial of AZT
o Various cancer treatments
o 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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