Lecture 16-19: Interventional Studies Flashcards
1
Q
Name the more important factors of the research evidence pyramid.
Star the ones that are considered true studies
A
- Meta Analyses
- Systematic Reviews
- Pragmatic Studies* and Interventional Studies *
- Cohort*
- Case Control*
- Cross Sectional*
- Ecological*
- A few more, and the last two Not conducted on humans
- Animal Research
- In vitro Research
2
Q
Describe the elements of an Interventional Study
A
- Interventional study designs considered “experimental”
- Investigator-selects interventions (exposure)
- There IS researcher-forced group allocation!!!
- Randomization processes commonly utilized to accomplish this step
3
Q
Describe the elements of an observational study
A
Observational study designs considered “natural”
- Researchers “observe” subject-elements occurring naturally or selected by individual (naturally or freely)
- Useful for unethical study designs using forced interventions
- Most observational study designs are not able to prove CAUSATION
- There is NO researcher-enforced group allocation!!!
4
Q
What are keywords used to indicate a clinical study?
How does it compare to observational
A
- Clinical Trial, Clinical Study, Experimental Study, Human Study, Investigational Study. It is NOT the only DESIGN for these terms for studies
- Key Difference (from Observational Studies):
- INVESTIGATOR selects “interventions” AND allocates study subjects to forced-intervention groups
- More “rigorous” in ability to show cause-and-effect
- Can demonstrate CAUSATION
5
Q
How does the study designs for increasing evidence differ between observational and interventional studies?
A
Interventional: Pre-Clinical (Phase 0), Phase I, Phase II, Phase III, Phase IV
Observational: Case Reports, Cross-Sectional, Ecological, Case Control, Cohort
6
Q
Describe the difference between Pre-Clinical and Phase 0
A
- Pre-Clinical (prior-to human investigation)
- ‘Bench’ or animal research
- Phase 0 (exploratory Investigational New Drug)
- Very small N (
7
Q
Describe Phase I of an Interventional Study
A
Phase 1 (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 (e.g., usually just a few weeks)
8
Q
Describe Phase II of an interventional study
A
Phase 2 (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
- Short-to-Medium duration (weeks to a few months)
- Likely to have narrow inclusion criteria
9
Q
Describe Phase III of an interventional study
A
Phase 3 (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)
10
Q
Describe Phase IV of an Interventional Study
A
Phase 4 (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/Survey’s also used in Observational design
- e.g.: FDA’s MedWatch/FAERS/VAERS programs
11
Q
What are the advantages and disadvantages of interventional studies?
A
- Advantages of Interventional Trials (vs. other designs)
- Cause precedes effect (CAN DEMONSTRATE CAUSATION)
- Only design-family used by FDA for “approval” process (on-label)
- Disadvantages of Interventional Trials (vs. other designs)
- Cost oComplexity/Time (development/approval/conductance)
- Ethical considerations (Risk vs. Benefit evaluation)
- Generalizability (a.k.a.; EXTERNAL VALIDITY) – Is study population similar to general population and will methodology and findings be applicable to them?
12
Q
Define a Simple Interventional Study Design
A
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 a time
13
Q
Define a Factorial Interventional Design
A
- Divides (randomizes) subjects into ≥2 groups AND THEN FURTHER sub-divides (randomizes) each of the GROUPS into ≥2 additional sub-groups
- Used to test MULTIPLE hypotheses (questions) at the same time
- Improves efficiency for answering clinical questions
- Increases study population sample size (due to increased group #)
- Increases complexity (which may be a barrier to recruitment)
- Increases risk of drop outs (due to complexity), and
- May restrict generalizability of results
- Numerical representation of # of groups and # of divisions (e.g., 2x2 or 3x3x2)
14
Q
Describe a Parallel Interventional Study
A
- Groups simultaneously and exclusively managed
- No Switching of intervention groups after initial randomization - All Simple and Factorial study designs are also Parallel
15
Q
Describe a Cross-Over Interventional Study
A
Cross-Over (a.k.a.; Self-Control)
- Groups serve as their own control by crossing over from one intervention to another during the study
- Allows for smaller total ‘N’ (sample size)
- Each patient contributes additional data
- BETWEEN and WITHIN comparisons are also possible
16
Q
Describe Run-In and Lead-In phase
A
- Assessing placebo-effects, Hawthorne-effects and compliance before study begins:
- ‘Run-In’ / ‘Lead-In’ Phase
- 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)
17
Q
What are the disadvantages of a cross-over design?
A
- 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
18
Q
What are the outcomes/endpoints of interventional study designs? (Primary, Secondary, Composite)
A
- Primary
- Most important, key outcome(s)
- Main research question (hypothesis) used for developing/conducting study
- Secondary / Tertiary / etc…
- Lesser importance yet still valuable
- Possible for future hypothesis generation
- Composite
- 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
19
Q
What are POEPs?
A
Patient-Oriented-Endpoints (most clinically relevant)
Examples include: Death, Stroke, or Myocardial infarction, Hospitalization, or Preventing need for dialysis
20
Q
What are DOE’s
A
- Disease-Oriented Endpoints: (surrogate markers) (elements used in place of evaluating Patient-Oriented (direct) Endpoints)
- Examples include: Blood pressure (for risk of stroke), Cholesterol (for risk of heart attack), Change in SCr (for worsening renal function)
21
Q
In an interventional study, what two types of sample selection or group allocation are available? Describe each.
A
- 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
- Random (most common utilized)
- Subjects DO have an equal probability of being assigned to each intervention group
- Random-number generating programs
22
Q
Describe randomization in interventional study designs
A
- Purpose: TO MAKE GROUPS AS EQUAL AS POSSIBLE; based on known and unknown important factors (confounders)
- Attempts to reduce systematic differences (bias) between groups which could impact results/outcomes
- Table 1 customarily used to show group characteristics
- Equality of groups Not Guaranteed!
- Documentation of equality of groups (effectiveness of randomization process) reported in 1-of-several locales:
- p values shown in table-format
- p values not shown but text-statement given in key of table
- p values not shown but text-statement given in article
23
Q
Give examples and describe the forms of randomization
A
- Simple
- Equal probability for allocation within one of the study groups
- Blocked
- Ensures balance within each intervention group
- When researchers want to assure that all groups are equal in size
- Stratified
- Ensures balance with known confounding variables
- Examples: gender, age, disease severity/duration, comorbidities
- Can also pre-select levels to be balanced within each interfering factor (confounder)
24
Q
What are the 3 types of interventional study design Masking
A
- Single-Blind
- Study subjects are not informed which intervention they are receiving (but clinicians/researchers are!)
- Double-Blind
- Neither investigators nor study subjects are informed which intervention each subject is receiving
- Open-Label
- Everyone knows which intervention each subject is receiving
25
Q
What are the forms of blinding in study masking
A
- Placebo (“Dummy” therapy)
- Inert treatments made to look identical in all aspects to the active treatments
- Dosage form, dosing frequency, monitoring, therapy requirements, etc…
- *Double-Dummy – more than 1 placebo used!!!!
- Placebo-effect
- Improvement in condition; by power of suggestion & due to the care being provided
- Can be as large as 30-50%!
- Hawthorne-effect
- Desire of study subject to “please” investigators by reporting positive results (improvement), regardless of treatment allocation
- Desire for positive outcome to process
26
Q
What is post-hoc sub-group analysis?
A
- Not accepted as appropriate, by most, when not prospectively planned
- “Data-Dredging” or “Fishing”
- Reduced Power & Increases risk of Type 2 error (more later in course)
- Is accepted as appropriate, by most, when it is prospectively planned, or performed for hypothesis generation and development of future studies
27
Q
What is another important factor of proper study designs relating to drop-outs and add-ins?
A
- Sample Size Determination (more in a future lecture…)
- ADD IN anticipated drop-out or loss to follow-up rates
- Managing Drop-Outs/Lost-To-Follow-ups:
- Include them anyway
- INTENT(ION)-TO-TREAT (most conservative decision)
- Examples of Procedures:
- Last known assessment (observation) used for (carried forward) all subsequent, yet missed assessments (LOCF)
- Convert all subsequent yet missed assessments for a subject to a null-effect (no benefit)
28
Q
What is the impact of a drop-out decision
A
- Impact of Drop-Out Decisions:
- Intent(ion)-to-Treat results in the following:
- Preserves randomization process
- Preserves baseline characteristics and group balance at baseline which controls for known and unknown confounders
- Maintains statistical power (original sample size)
- Per-Protocol results in the following:
- Biases estimates of effect (commonly over-estimates effects)
- Reduces generalizability!
29
Q
What are the two ways to manage drop-outs/lost-to-follow-ups
A
- Ignore them (include only compliant or completing subjects)
- PER-PROTOCOL or EFFICACY-ANALYSIS
- Compliance must be pre-defined
- Customarily set at 80-90% compliance with study protocol
- Results in Biases estimates of effect (commonly over-estimates effects)
- Reduces generalizability!
- Treating them “as treated”
- AS-TREATED
- Ignores group assignments;
- Allows subjects to switch groups and be evaluated in group they moved to, end in, or stay in most
30
Q
How does one assess and improve adherence?
A
(Adherence: Compliance)
- 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
