This document provides an overview of clinical trials, including their purpose, classifications, terminology, design, phases, ethics, and protections for participants. Some key points: - Clinical trials test interventions like drugs or procedures and compare them to standard practices or placebos. They progress through phases to test safety and effectiveness. - There are three main types of research studies: observational studies that compare groups, analytic studies that test therapies, and clinical trials which are considered the "gold standard" experimental study. - Protections like informed consent and institutional review boards ensure ethical treatment of human subjects and that risks are reasonable compared to potential benefits. Oversight protects participants' rights and welfare.

1. Understanding
Clinical Trials
Developed by Sara Back, NP
Bronx-Lebanon Hospital Center

2. 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. 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. 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 orThe study of the distribution of a disease or
condition in a population and the factors thatcondition in a population and the factors that
influence that distribution.influence that distribution.

5. Classifications of Research Studies:
Three Main Types
Observational Studies:Observational Studies:
• Groups are studied & contrasts made between groups
• The observed data collected are analyzed
Analytic Studies:Analytic Studies:
• Also called Experimental
• Study the impact of a certain therapy
• Ultimately the investigator controls factor being studied
Clinical Trial: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. 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. 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. Basic Research Terminology
• Retrospective:Retrospective: Refers to time of data collection
• Prospective:Prospective: Refers to time of data collection
• Case Control Study:Case Control Study: Persons w/ disease & those w/out are
compared
• Cohort Study:Cohort Study: Persons w/ and/or w/out disease are followed over
time

9. Terminology (Cont.)
• Cross-sectional Study:Cross-sectional Study: Presence or absence of exposure to possible
risk factor measured at one point in time. Prevalence obtained.
• Prevalence:Prevalence: The # of new cases and existing cases during specified
time period.
• Incidence:Incidence: The # of NEW cases per unit of a population at risk for
disease occurring during stated time period.

10. 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. Historical Minute
First “Clinical Trials”
Historical Highlights of Drug TrialsHistorical 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. 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. 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. 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. Simplified
• Randomized:Randomized: Schemes
used to assign
participant to one
group
o Ex: Every 3 gets higher
dose
• Nonrandomized:Nonrandomized: All
with Hep. C = cases;
others = controls
• Protocol:Protocol: Study design
- instructions
• Blinded:Blinded: Participants do
not know if in
experimental or control
group
• Double Blinded:Double Blinded:
Participants AND staff do
not know group
assignment
• Placebo:Placebo: Inactive pill w/
no therapeutic value

16. 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. 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. 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. Phases of Clinical Trials
• Phase I:Phase I: Small group [20-80] for 1st time to evaluate safety, determine
safe dosage range & identify SE
• Phase II:Phase II: Rx/tx given to larger group [100-300] to confirm effectiveness,
monitor SE, & further evaluate safety

20. Phases of Clinical Trials (cont.)
• Phase III: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: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. Summary of Phases I-III
# Subs.# Subs. LengthLength PurposePurpose % Drugs% Drugs
SuccessfullySuccessfully
TestedTested
Phase IPhase I 20 – 100 Several
months
Mainly Safety 70%
Phase IIPhase II Up to
several
100
Several
months-
2 yrs.
Short term
safety; mainly
effectiveness
33%
PhasePhase
IIIIII
100s –
several
1000
1-4 yrs. Safety, dosage
& effectiveness
25-30%

22. Ethics of Clinical Trials:
Protection of Participants
3 ethical principles guide clinical research:
• Respect for Persons:Respect for Persons: Treatment of person as autonomous
• Beneficence:Beneficence: Issue re: potential conflict between good of society vs.
individual
• Justice:Justice: Treatment of all fairly & all equally share benefits & risks

23. 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. 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. Human Subjects’ Protection
IRB responsible for such tasks: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. 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):IRB Responsibilities (continued):

27. 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. 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. 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. 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. 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. Vulnerable Populations
Groups thought not to have autonomy to give informed
consent:
•children
•mentally impaired, individuals with dementia
•Prisoners
OROR
Who may be unduly influenced to participate:
•students
•subordinates
•pregnant women (actually, the fetuses)
•patients (care-giver vs. researcher)

33. 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. Inclusion in Clinical Trials
• NIH Revitalization Act of 1993: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. 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. 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. Participation in Clinical Trials
Why Some Participate:Why Some Participate:
•Give back to society
•Exhausted all other txs
•Health care services
•Payment & incentives
•Support
•Others??
Why Some Do Not?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. 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. 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. 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. 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