Class 16-19 Flashcards
(38 cards)
Interventional study design
***CAN prove causation
Considered “Experimental”
Investigator selects interventions (exposures)
There IS researcher forced-group allocation
**Randomization processes used to accomplish this step
Other terms: Clinical trial, clinical study, experimental study, human study, investigational study
-KEY DIFFERENCE:
Investigator selects “interventions” and allocated study subjects to forced-intervention groups
More “rigorous” in ability to show cause-and-effect–>can demonstrate causation
Observational study design
**CANNOT prove causation (most)
Study design considered “natural”; researches observe subject-elements occurring naturally or selected by individual
Useful for unethical study designs using forced interventions
There is NO researcher-forced group allocation
Levels of Interventional Study Designs
In increasing evidence: Pre-Clinical (Phase 0) Phase 1 Phase 2 Phase 3 Phase 4
Levels of Observational Study Designs
In increasing evidence: Case reports/series Cross-sectional Ecological Case-control Cohort
Pre-Clinical (Phase 0) of Interventional Study Designs
(Prior to human investigation)
“Bench” or animal research
Phase 0 of Interventional Study Designs
(Exploratory Investigational New Drug)
Very small N (<20), healthy volunteers (or diseased patients (oncology)), first use in humans to access drug-target and pharmacokinetics in small (non-therapeutic) doses
Very short duration (usually just a few days)
Not looking at efficacy at this stage; primary purpose is: does it hit the target that it was intended to reach?
Phase 1 of Interventional Study Designs
(Investigational new drug)
Small N (20-80), healthy volunteers (or diseased), possibly first-time use in humans to assess dose escalation, safety, tolerance (pharmacokinetics)
Short duration (usually just a few weeks)
Phase 2 of Interventional Study Designs
(Investigational new drug; indication/population
Medium N (100-300), commonly utilize patients with condition of interest, used to expand on purpose of Phase 1 study but begins assessing efficacy in the diseased
Efficacy is primary reason for phase 2; will start looking at dose response at several different doses
Short-to-medium duration (weeks to months)
Likely to have narrow inclusion criteria
Phase 3 of Interventional Study Designs
(Investigational new drug; indication/population)
Large N (500-3,000), used in patients with condition of interest, continues assessing short-to-intermediate safety, with primary purpose to assess efficacy
Broader inclusion criteria; more clinically relevant (yet still possible to limit generalizability)
Longer duration (months to years)
Normally have already figured out dose once we get to Phase 3
Phase 4 of Interventional Study Designs
(Post-marketing/post-FDA-approval)
Larger N (1000’s); longer-term effects (risks & benefits)in diseased patients (expanded use population; age, ethnic)
~Interventional or observational design
~Registries/surveys are also used in observational design
Advantages of Interventional Trials
Cause precedes effect (can demonstrate Causation)
Only design-family used for FDA for “approval” process (on-label)
Disadvantages of Interventional Trials
Cost
Complexity/Time (development/approval/conductance)
Ethical considerations (Risk vs. Benefit evaluation)
Generalizability (aka: External Validity) – Is study population similar to general population and will methodology and findings be applicable to them?
Explanatory vs. Pragmatic Interventional Studies
Pragmatic are studies that loosen the inclusion criteria; less restrictive, more realistic of population; allow physicians to use the results of the study
Designs of Interventional studies
Simple
Factorial
Parallel
Cross-Over
Designs of Interventional Studies: Simple
Divides (randomizes) subjects exclusively into >=2 groups
A single randomization process; no subsequent randomized divisions
Commonly used to test a single hypothesis (question) at at time
Take the group of ppl who meet the criteria and want to participate and then force them into groups—1 group allocation
Designs of Interventional Studies: Factorial
Divides (randomizes) subjects into >=2 groups and then further sub-divides (randomizes) each of the groups into >=2 additional sub-groups
Groups—subgroups
**Used to test multiple hypotheses (questions) at the same time
Improves efficiency for answering clinical questions
Increases study population sample size (due to inc. group #)
Increases complexity (which may be a barrier to recruitment)
Increases risk of drop outs (due to complexity)
May restrict generalizability of results
Designs of Interventional Studies: Parallel
Groups simultaneously and exclusively managed
No switching of intervention groups after initial randomization
All simple and factorial study designs ARE ALSO PARALLEL
Designs of Interventional Studies: Cross-Over
AKA Self-Control
Best for chronic, long-standing conditions
Groups serve as their own control by crossing over from one intervention to another during the study
Allows for a smaller total ‘N’ (sample size) because each patient contributes additional data
Allows for Between- & and Within-Group comparisons
Run-In/ Lead-In Phase of Interventional Study Design
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)
Can be a trial run/practice of the study – can look at compliance and adherence of the participants (with them not knowing it is a practice)
Disadvantages of Cross-Over design
Only suitable for long-term conditions which are not curable or which treatment provides short-term 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
Interventional study designs: Outcomes/Endpoints
1) Primary
- Most important, key outcome(s)
-Main research question (hypothesis) used for developing/conducting study
2) Secondary/Tertiary/etc…
- Lesser importance yet still valuable
-Possible for future hypothesis generation
3) Composite
- Could be considered the Primary outcome, and if so, then secondary outcomes may be the individual outcome elements from Composite
Examples of Patient-Oriented Endpoints
POEMS; most clinically relevant:
- Death
- Stroke or MI
- Hospitalization
- Preventing need for dialysis
Examples of Disease-Oriented Endpoints
DOE’s; surrogate markers; elements used in place of evaluating Patient-Oriented (direct) endpoints
- Blood pressure (for risk of stroke)
- Cholesterol (for risk of heart attack)
- Change in SCr (for worsening renal function)
Sample-Selection & Group Allocation: Non-Random
Subjects don’t have an equal probability of being selected or assigned to each intervention group (e.g. Convenience Sampling/Non-probabilistic allocation)
- Patients attending morning clinic assigned to group 1, patients attending afternoon clinic assigned to group 2
- Patients attending clinic on odd days of the month assigned to group 1, patients attending clinic on even days assigned to group 2
- The first 100 patients admitted to the hospital
