Understanding Clinical Trials

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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 ones 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 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 Helmonts proposal for a therapeutic
  trial of bloodletting for fevers 1628
• Dr. Linds, a ship surgeon, trial of oranges
  limes for scurvy 1747

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Historical MinuteFirst 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 Schemes used to assign participant to
  one group
• 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

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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 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 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
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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
• 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 MinuteOrigin 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 Minute10 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 ConsentA 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 subjects 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
• Women minorities are to be included in all
  human subject research
• They are to be included in Phase III trials to
  allow sufficient power to note differences
• Cost cannot be a barrier
• 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 TrialsUse 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
• 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

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Taking Part in Research StudiesQuestions 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
• Protocol 076 ? HIV perinatal transmission
• 1st trial of AZT
• Various cancer treatments
• 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