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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 one’s 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 The study of the distribution of a disease or condition in a population and the factors that condition in a population and the factors that influence that distribution.influence that distribution.
NY/VI AETC
Classifications of Research Studies: Three Main Types
Observational Studies:Observational Studies:• Groups are studied & contrasts made between groups• The observed data collected are analyzedAnalytic Studies:Analytic Studies:• Also called Experimental• Study the impact of a certain therapy• Ultimately the investigator controls factor being studiedClinical 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
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
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: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
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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.
NY/VI AETC
Historical MinuteFirst “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]
NY/VI AETC
Historical MinuteFirst “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
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
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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
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
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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
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: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
NY/VI AETC
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.
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Summary of Phases I-III
# Subs. # Subs. LengthLength PurposePurpose % Drugs % Drugs Successfully Successfully 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%
Phase Phase IIIIII
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: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
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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"
NY/VI AETC
Human Subjects’ ProtectionIRB 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
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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):
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
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Vulnerable Populations
Groups thought not to have autonomy to give informed consent:
• children
• mentally impaired, individuals with dementia
• Prisoners
OR 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 subject’s native lang.• Prisoners: only some types of research
allowed
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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 researcho They are to be included in Phase III trials to
allow sufficient power to note differenceso Cost cannot be a barriero 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: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
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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 transmissiono 1st trial of AZTo Various cancer treatmentso Development of other HIV related
medications like PIs
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The Impact of Studies
Other clinical trials have not been assuccessful 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