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Understanding Clinical Trials

Developed by Sara Back, NP

Bronx-Lebanon Hospital Center

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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 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.

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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

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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: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.

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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]

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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

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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: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

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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

• 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

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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: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

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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%

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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"

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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):

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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

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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 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: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

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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 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?

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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 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)

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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