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Epidemiology > Lecture 16-19: Interventional Studies > Flashcards

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
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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
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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!!!
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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
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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

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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 (
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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)
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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
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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)
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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
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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?
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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
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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)
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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
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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
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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

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