Interventional Studies Flashcards
What are some other terms that can be used for interventional studies?
- Clinical trial
- Clinical study
- Experimental study
- Human study
- Investigational study
Key difference between interventional and observational studies
- Can show causation
- investigator selects interventions and allocates study subjects to forced intervention groups
What are the different aspects that determine the different phases of interventional studies?
- Purpose/Focus
- Population studied (healthy/diseased)
- Sample size
- Duration
What does the duration of the study depend on?
- the disease or the research question being asked
What is the purpose of the pre-clinical stage?
- helps drive the hypothesis
Phase 0
- Asses drug-target actions and pharmacokinetics in non-therapeutic/non-diagnostic doses
- Healthy volunteers (or cancer patients)
- Very small (<20)
- Very short duration (single dose to a few days)
Phase 1
- Asses safety/tolerance and pharmacokinetics of one or more dosages
- Healthy or disease volunteers (depending on disease)
- Small (20-80)
- Short duration (a few weeks)
What are some aspects of pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Excretion
Phase 2
- Asses effectiveness (while still looking at safety and tolerability)
- Diseased volunteers
- Larger N (100-300)
- Short to medium duration (few weeks to a few months)
Phase 3
- asses effectiveness (safety and tolerability as well)
- diseased volunteers
Uses the different perspectives - Larger N (300-500)
- Longer duration (few months to a year)
Phase 4
- post FDA approval
- Assess long term safety, effectiveness and optimal use (risks/benefits)
- Diseased volunteers (comorbidities)
- population N (100,000 - millions)
- Longer duration (many years to decades)
Advantages of Interventional Trials
- Cause precedes effect (can demonstrate causation)
- Only design-family used for FDA approval process
Disadvantages of Interventional Trials
- Cost
- Complexity/Time
- Ethical considerations
- Generalizability
Simple Interventional studies
- Divides (randomizes) subjects once
- Tests a single hypothesis at a time
Factorial Interventional Studies
- Divides (randomized) into groups and then further sub-divides each of the groups into additional sub-groups
- Used to test multiple hypotheses at the same time
What are some characteristics of factorial interventional studies?
- Improves efficiency for answering clinical questions
- Increases study population sample size
- Increases complexity (which may be a recruitment barrier)
- Increases risk of drop outs
- May restrict generalizability results
Parallel Interventional Studies
- groups simultaneously and exclusively manages
- no switching of intervention groups after initial randomization
- All simple and factorial study designs are also parallel
Cross-Over (Self-Control) Interventional Studies
- Groups serve as their own control by crossing over from one intervention to another during the study
- Allows for smaller sample size
What is a washout period?
Refers to the break that happens after a certain time frame in a crossover study. Before the groups are switched.
Run-In/ Lead-in Phase
- determining a new baseline
- cleaning out and baseline establishment before a study starts
Can also be a practice and dry run before the actual study
Disadvantages of Cross-Over Design
- only suitable for long term conditions that are not curable or which treatment provides short term relief
- Duration of study for each subject is longer
- Carry-over effects during crossover
- Treatment-by-period interaction
- Smaller N requirement only applicable if within-subjects variation less than between-subjects variation
- Complexity in data analysis
Primary Outcome
- Most important, key outcome
- Main research question for developing/conducting study
Secondary/Tertiary etc. Endpoints
- Lesser importance but still valuable
- Possible for future hypothesis generation
E.g. Side Effects
Composite Endpoints
- Combines multiple endpoint into a single outcome
Can also be called group outcome
Examples of Patient oriented Endpoints
- Death
- Stroke or MI
- Hospitalization
- Preventing need for dialysis
Examples of disease-oriented endpoints
- Blood pressure (for risk of stroke)
- Cholesterol (for risk of heart attack)
- Change in SCr (for worsening renal function)
Non-Random Sample Selection & Group Allocation
Subjects don’t have an equal probability of being selected or assigned to each intervention group
Random Sample Selection and Group Allocation
Subject do have an equal probability of being assigned to each intervention group
What is the purpose of randomization?
- to make groups as equal as possible; based on known and unknown important factors.
- Equality of groups in not guaranteed
Forms of Randomization
- Simple
- Blocked
- Stratified
Simple Randomization
- Equal probability for allocation within one of the study groups
Blocked Randomization
Ensures balance within each intervention group.
Stratified Randomization
Ensure balance with known confounding variables
- gender, age, disease etc
- can preselect levels to be balance within each interfering factor
Types of Masking
- Single-blind
- Double-blind
- Open-Label (unmasked/unblinded)
Single-blind
Subjects not informed but researchers are
Double blind
Neither the subject nor the researcher knows which groups the subjects are in
Open-Label
Study subjects and researcher both know which intervention is being received
Forms of Blinding (Masking)
- Placebo (dummy therapy)
- Placebo-effect
- Hawthorne effect
Placebo
- Inert treatments made to look identical to active treatments
Placebo Effect
Improvement in condition by power of suggestion of being treated
Hawthorne Effect
Study subjects change their behavior solely due to awareness of being studied/observed
Post-hoc sub-group analysis
- Not accepted as appropriate, by most, when not planned before
Intention to Treat
Uses the last know assessment carried forward when a patient is lost to follow-up
Also can use the baseline moving forward
What does intention-to-treat result in?
- preserves randomization process
- preserves baseline characteristics and group balance at baseline which controls for known and unknown confounders
- maintains. Statistical power
How can you manage drop-outs and lost-to-follow-ups?
- Ignore them - include only those that complied
- Treating them as treated - if they happen to be on the drug that you are looking at you use those results
Assessing Adherence (compliance)
- Drug levels (multiple useful sites)
- Pill counts at each visit
- Bottle counter-tops
Methods of Improving Adherence (Compliance)
- Frequent follow-up visits/Communications
- Treatment alarms/notifications
- Medication blister packs or dosage containers
