16-19 Interventional Study Designs Flashcards
List the other terms used for interventional studies.
- Clinical trial
- Clinical study
- Experimental study
- Human study
- Investigational study
What is the key difference between observational and interventional studies?
• Investigator selects “interventions” and allocates study subjects to forced-intervention groups
• More “rigorous” in ability to show cause-and-effect
o Can demonstrate causation
List and describe the phases of interventional studies.
PRE-CLINICAL (prior to human investigation)
o Bench and animal research
PHASE 1 (new drug/device/procedure)
o Small N (~20-80), healthy volunteers tor used for the first time in humans to assess safety/toxicity, dosing and even pharmacokinetics in population of interest (diseased)
- Short duration (e.g., usually just a few days or weeks or a couple of months)
PHASE 2 (new drug/device/procedure, indication or study population)
o Larger N, (~100-300), commonly utilize patients with condition of interest, used to expand on purpose of Phase 1 study (safety) but also to begin assessing efficacy in diseased population
Short-to-medium duration (a few to several months)
Likely to have a narrower inclusion criteria
PHASE 3 (new drug/device/procedure, indication or study population)
o Even larger N (~1000-3000), used in patients with condition of interest to continue determination of safety, with primary purpose to assess efficacy
Longer duration (many month to a year (or a few years))
Superiority vs. Noninferiority vs. Equivalency formats
PHASE 4 (post-marketing)
o Long-term effects (risks and benefits) in a large population of diseased patients (expanded use population (age, ethnic))
Registries, Survey’s (e.g., FDA’s MedWatch/FAERS/VAERS programs)
What are the advantages and disadvantages of interventional studies?
Advantages
• Cause precedes effect (shows Causation)
• Only design used by FDA for “approval” process (on-label)
Disadvantages
• Cost
• Complexity/Time (development/approval/conductance)
• Ethical considerations (Risk vs. Benefit evaluation)
• Generalizability (a.k.a.; External Validity)
o Is study population similar to general population and will methodology and findings be applicable to them?
Compare pragmatic versus explanatory studies.
• Explanatory has presubscribed playbook that you must abide by. It is not flexible for real clinical practice. They are so restrictive in who can participate. Typically seen in phases 2 and 3.
• Pragmatic studies are still in the family of interventional studies. Clinically applicable. Less restrictive on inclusion criteria.
o Never use placebo - common sense medicine
o Let in regular people - multiple comorbidities, on multiple meds
o Allow physicians to use own clinical judgement to treat patients
o Lose researcher’s control how physician prescribes medication
o Lose lack of other confounding variables - introduced again
• Many researchers will have an explanatory interventional study from phase 1-3, but may (don’t have to) switch to a pragmatic study in phase 4 for more long term benefits/harm, but also for an increase in external validity for medical application purposes - can more patients use it?; incorporate multiple conditions;
What are the 4 types of design?
Simple
Fractional
Cross-over
Parallel
Define a simple study.
o Divides (randomizes) subjects exclusively into > 2 groups A single randomization process; no subsequent randomized divisions o Commonly used to test a single hypothesis (question) at a time
Define a fractional study.
o Divides subjects into > 2 groups and then further additionally sub-divides (randomizes) each of the groups in to > 2 sub-groups
Numerical representation of number of groups and number of divisions (e.g., 2x2 or 3x3x2)
o Used to test multiple hypotheses at the same time (increases sample size requirement)
Improves efficiency for answering clinical questions
Increases study population sample size (due to increase group #)
Increases complexity (which may be a barrier to recruitment)
Increases risk of drop outs (due to complexity), and
May restrict generalizability of results
Define a parallel study.
o Groups simultaneously and exclusively managed
o No switching of intervention groups after initial randomization
All simple and factorial designs are also parallel
Define a cross-over study.
o Groups serve as their own control by crossing over from one intervention to another during the study
Allows for small total “N” (sample size)
• Each patient contributes additional data
o Between and within group comparison possible
What are the disadvantages of a cross-over study?
Only suitable for long-term conditions which are not curable or which treatment provides short-terms relief
Duration of study for each subject is longer
Carry-over effects during cross-over (wash-out required; which prolongs study duration)
Treatment-by-Period interaction
• Differences in effects of treatments during different time periods
Smaller N requirement only applicable if within-subjects variation less than between-subjects variation
Complexity in data analysis
What is a run in or lead in phase?
o All study subjects blindly given one or more placebos for initial therapy (defined time period) to determine a new base-line of disease (standardization)
Can assess study protocol compliance
Can “wash-out” existing medication
• Reduces at least 1 possible common exclusion criteria
Can determine amount of placebo-effect (new-baseline)
What are the different types of outcomes?
Primary Secondary/Tertiary Composite Patient-Oriented Endpoints Surrogate markers
What a composite outcome?
Combines multiple endpoints into a single outcome
Could be considered the Primary outcome, and if so, then secondary outcomes may be the individual outcome elements from Composite
What is a primary outcome?
Most important, key outcome(s)
Main research question (hypothesis) used for developing/conducting study
