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29 Cards in this Set
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Describe a Phase I Study Design for Clinical Trials Phase I: Researchers test a new ____ or ____ in a ____ group of people for the first time to evaluate its ____ , determine a safe ____ ____ , and identify ____ . |
Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. |
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Describe a Phase II Study Design for Clinical Trials Phase II: The drug or treatment is given to a ____ group of people to see if it is ____ and to further evaluate its ____ . |
Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety. |
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Describe a Phase III Study Design for Clinical Trials Phase III: The drug or treatment is given to ____ groups of people to confirm its ____ , monitor ____ , ____ it to commonly used treatments, and collect information that will allow the drug or treatment to be used ____ . |
Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. |
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Describe a Phase IV Study Design for Clinical Trials Phase IV: Studies are done after the drug or treatment has been ____ to gather information on the drug's effect in various ____ and any side effects associated with ____ - term use. |
Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long- term use. |
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Dose Escalation Design What phase is this design under? What does it determine? What is monitored? Type and level/grade of _____ specified in ____ Give an example of a dose escalation design. |
Phase I Determine maximum tolerated dose (MTD) Type and level/grade of toxicity specified in protocol Traditional 3+3 Design |
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Single-arm design
What phase is this design under? Usually how many patients? What does it assess? |
Phase II Usually < 100 patients Continued assessment of safety in addition to effectiveness |
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Multi-arm parallel design What phase is this design under? Name different types. Which is referred to as the "control" group? What does it assess? What does parallel refer to? |
Phase II Two or more treatment arms/groups Two-arm randomized controlled trial Three-arm randomized controlled trial Placebo or SOC (standard of care) Continued assessment of safety in additional to main interest in efficacy “Parallel” refers to the fact that each patient receives only one treatment and each treatment group proceed in parallel |
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Describe a Randomization design What does it ensure? Who does the randomization? |
Two or more treatment arms/groups Randomized Treatment Assignment Ensures that patients are assigned to study arms without bias (systematic differences in baseline characteristics) Independent, e.g. statistician, Centralized randomization for multi-site studies, Data coordinating center, pharmacist, Many computer programs |
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Block Randomization For _____ number of patients, randomization does not guarantee ______ number of patients in treatment and control group |
small, similar Could do randomization in blocks, e.g., for 40 patients a block size of 4 possible balanced combinations with 2 C (control) and 2 T (treatment) subjects are (TTCC, TCTC, TCCT, CTTC, CTCT, CCTT) blocks are randomly chosen to determine the assignment of all 40 subjects, e.g., one random block sequence: [TTCC / TCCT / CTTC / CTTC / TCCT /CCTT / TTCC / TCTC / CTCT / TCTC]) This ensures that there’s 20 subjects in both the control and treatment groups (equal-sized study groups) |
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Stratified Randomization What is important to balance? Examples of stratification factors? Only feasible with ____ factors |
It is important to balance baseline factors that may be associated with the response to treatment (prognostic factors) • E.g. age or baseline severity/illness Stratification factors – Stratified Randomization Two factors: male, female & age (<18, >=18) -> 4 strata/groups Separate randomization within each stratum Multisite study: Randomization within each study site (standard of care maybe different by site) Only feasible with a few factors; 2 or 3 especially for small trials Common example: (a) stratified by study site (b) block randomization within site |
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Blinding What are other sources of bias? Describe single-blinding Describe double-blinding What is the most "rigorous" design? |
There are other sources of bias during the study (after randomization), e.g. Patients knowing they are on placebo may drop out early For investigators, outcome assessment is more objective if s/he does not know which treatment group patient is on (e.g., subconscious bias) Single-blinding means patient doesn’t which treatment s/he is on Double-blinding means neither patient or clinician knows ... Most “rigorous” design: Blinded, placebo-control |
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How should Unblinding Procedure be done? What is the gold standard of unblinding? |
Unblinding (breaking the code) should be done as specified I the protocol Ideally/gold-standard is to do this at the end of the study / study close This is not the same as when each patient complete his/her participation (e.g., 8 weeks of treatment for 100 patients recruited over 4 years) |
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Any premature unblinding should be _______ an _______ accordingly (e.g., sponsor) Stated in final study publication as potential source of _______ |
Documented an reported accordingly (e.g., sponsor) Stated in final study publication as potential source of bias |
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Randomized Placebo-Controlled Placebo group should have minimal ______/______(“______effect”) Main use: Show drug/device (investigational product) have improved ______ over a ______ control Also, design is very useful for understanding ______ and ______effects (commonly “____________”) Design typically used for treatment administered for a ______ time period |
minimal benefit/efficacy (“placebo effect”) Show drug/device (investigational product) have improved efficacy over a placebo control understanding safety and adverse effects (commonly “blinded randomized placebo-control”) for treatment administered for a short time period |
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Describe Crossover Design What is critical to avoid crossover effects? |
Patients randomized to a sequence of treatment Example: 2 treatments (A=treatment and B=placebo), 2 periods Patients randomized to the sequence AB or BA Wash out period in between treatments (A and B) is very critical to avoid crossover effects Note: also short treatment period |
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Limitations to Crossover Design ______ effect; Try to avoid by design with adequate ______ One must understand the disease; it should be ______ /condition and treatment doesn’t “cure” condition
Advantages Each subject “serving as own ______ ” More ______ (fewer patients needed) to estimate treatment efficacy compared to parallel design All patients will get “______ ” intervention/treatment |
Limitations Carryover effect; Try to avoid by design with adequate washout One must understand the disease; it should be stable/condition and treatment doesn’t “cure” condition
Advantages Each subject “serving as own control” More efficient (fewer patients needed) to estimate treatment efficacy compared to parallel design All patients will get “active” intervention/treatment |
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Describe Phase III Sample size? What is needed for management of data, data collection, randomization, interim analysis etc. What type of duration? What is challenging about this design?
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Larger sample size, often multi-center/site e.g. > 300 people Need data coordinating center for management of data, data collection, randomization, interim analysis etc. Longer duration Expensive – logistically most challenging |
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Phase IV What type of surveillance? Duration and type of study? When is it conducted? What type of study design is typically used? What happens if AEs are discovered? |
Postmarketing surveillance, safety surveillance (pharmacovigilance) long-term, longitudinal studies After FDA approval Study design used typically observational, epidemiological methods, e.g., case-control, case series design; multivariate modeling (“uncontrolled”/no control – not randomized controlled trial) Adverse effects discovered in Phase IV may lead to restricted drug use or being withdrawn from market (e.g., Vioxx) |
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Equivalence/Non-inferiority Studies Treatment A is less ______ and have similar benefit (efficacy) compared to standard treatment B We might tolerate a small reduction in ______ but we gain in having much less ______ side effects Study null hypothesis: Treatment A is less efficacious than standard treatment B by a ______ amount Δ (alternative hypothesis is that A=B) Δ is call the______ |
Treatment A is less toxic and have similar benefit (efficacy) compared to standard treatment B We might tolerate a small reduction in efficacy but we gain in having much less adverse side effects Study null hypothesis: Treatment A is less efficacious than standard treatment B by a small amount Δ (alternative hypothesis is that A=B) Δ is call the non-inferiority margin |
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Bioequivalence Clinical Trials A CT whose objective is to demonstrate that ___ or ____ formulations of the same drug have comparable _______ Bioavailability = ___ and ___ an active drug gets to the ___ (and hence available to tissue and target organ) |
A CT whose objective is to is to demonstrate that 2 or more formulations of the same drug have comparable bioavailability Bioavailability = extent and rate an active drug gets to the bloodstream (and hence available to tissue and target organ) |
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Describe Observational studies Which concepts do and do not apply? |
No intervention All concepts apply, except randomization, blinding etc. |
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Studies that's not Clinical Trial “_________” studies, e.g., to assess _________? |
“Laboratory” studies, e.g., to assess mechanism? selection, raters, blind biosample sample labeling etc.) |
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Adaptive Designs Adaptive designs in clinical trials may allow for changes in: ______/______criteria Study ______, ______ and treatment ______ ______ method
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Inclusion/exclusion criteria Study dose, end points and treatment durations Analysis method |
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Adaptive Designs: A ________ (GSD) is an adaptive/flexible design that allows for early _______ of a trial based on interim analysis for: _______ , _______ , _______ Statistician work with _______ to plan ahead these data _______ events |
A group sequential design (GSD) is an adaptive/flexible design that allows for early stopping of a trial based on interim analysis for: Safety, Efficacy, Futility Statistician work with investigator to plan ahead these data monitoring events |
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Data Safety and Monitoring Board (DSMC) What do they play a role in? What is the common misconception? |
Reviewing baseline data, safety and toxicity data, effectiveness of randomization Early study termination Planned efficacy analysis Etc., a DSMC charter is created prior to start May make recommendation including early study termination, study protocol modification Common misconception (still...) DSM Plan: “The PI will review all data...” (w/o independent DSMC) |
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Protocol Development: Main Elements of Protocol The protocol sets the ______ by which study will be conducted
List the content |
The protocol sets the standards by which study will be conducted Objectives: primary, secondary etc. must be clearly defined Background: Justification for pursuing the objectives; include biologic rationale, clinical observation, state-of-knowledge, response to “SOC” or preliminary data to justification statistical consideration and study design Investigational product/drug information Stage definition (oncology) Recognized efficacy parameters for the given area; RECIST for solid tumors; CGI- Clinical Global Impression e.g. autism Trial design Safety evaluation to protect subject: med hist., baseline data at enrollment, AE reporting, clinical/lab tests – area-specific Ethics Data management Quality control and quality assurance procedures Appendix/Supplement |
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What goes into the amendments of the protocol? |
Sponsor and IRB approval |
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Why is data management important? |
Faulty data compromises studies |
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Study Reporting: CONSORT Standards What does CONSORT stand for? Why was it developed? How many items on the checklist? |
Consolidated Standards of Reporting Trials Developed to alleviate the problems arising from inadequate reporting of RCTs. 25-item checklist (first 8 ...) |
