2. 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
3. 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”
4. 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.
5. 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
6. 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
7. 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
8. 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
9. 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.
10. 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]
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. NY/VI AETC
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.
21. 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%
22. 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
23. 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
24. 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"
25. 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
26. 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):
27. 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
28. 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
29. 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
30. 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
31. 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
32. 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)
33. 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
34. 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
35. 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
36. 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
37. 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
38. 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?
39. 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 1st trial of AZT
o Various cancer treatments
o Development of other HIV related
medications like PIs
40. 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)
41. 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
