Classes 16-19 Interventional Study Design Flashcards
What type of study is most commonly read and the only type to prove causation?
Interventional studies
Name other terms used for interventional studies
Clinical trial Clinical study Experimental study Human study Investigational study
What are the phases of interventional studies?
Pre-Clinical Phase 1 Phase 2 Phase 3 Phase 4
What phase is prior-to human investigation and is usually associated with bench and animal research?
Pre-clinical
What phase does this describe? Small population (~20-80) Short duration Safety
Phase 1
What phase does this describe? Population size ~100-300 Safety and Efficacy Short-to-Medium duration (few to several months) Likely to have narrower inclusion criteria
Phase 2
What phase does this describe? Population size ~1,000-3,000 Duration of many months to a year (or few years) Safety, but primarily efficacy
Phase 3
What phase does this describe? Long-term effects Risks and Benefits Large population size Registries/Surveys
Phase 4
What are the advantages of interventional trials (vs. other designs)?
Cause precedes effect (shows causation) Only design used by FDA for “approval” process
What are the disadvantages to interventional studies (vs. other designs)?
Cost Complexity/Time (development/approval/conductance) Ethical considerations (risk vs. benefit eval) **Generalizability (aka External Validity)
What are the disadvantage of an “explanatory” interventional study?
They do not give you flexibility like you normally have in clinical practice They give you an exact playbook on the to play the game and as a clinician, you cannot deviate
How is a “pragmatic” interventional study less restrictive than an “explanatory” interventional study?
Pragmatic studies rarely use placebo More clinically relevant Let in real people, people that have real co-morbidities, people on other meds
What are the disadvantages of “pragmatic” interventional studies?
Researcher loses control of how physicians prescribe/manage patients Might introduce confounding Loss of control and rigidity
Describe a SIMPLE study design
Divides subjects into as many as 2 groups (single randomization process) Commonly used to test a SINGLE hypothesis
Describe a FACTORIAL study design
Divides subjects into two or more groups and then further randomizes Used to test multiple hypotheses at the same time Must increase population size
What are the benefits/disadvantages to a FACTORIAL study design?
Improves efficiency for answering clinical questions Increases study pop. sample size Increases complexity Increases risk of drop outs May restrict generalizability of results
Describe a PARALLEL study design
Groups simultaneously and exclusively managed No switching of intervention groups after initial randomization Includes all simple and factorial study designs
Describe a CROSS-OVER study design
Groups serve as their own control by crossing over from one intervention to another during the study Allows for small total N Each patient contributes additional data Between & Within group comparisons possible
Wash-out Phase
Period needed for groups to get their systems back to baseline
Define Lead-in/Run-in Phase
All study subjects blindly given one or more placebos for initial therapy to determine a “new” base-line of disease. Uses to assess for placebo-effects, Hawthorne-effect, and compliance before study begins
What can we assess/determine from the Lead-in/Run-in phase?
Can assess study protocol compliance Can “wash-out: existing medication Can determine amount of placebo-effect
List the 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 effect (requires wash-out) Treatment-by-period interaction Smaller N requirement only applicable if within-subjects variation less than between-subj. variation Complexity in data analysis
What study format is demonstrated in the graphic?
Simple, Parallel
Describe a Primary Outcome/Endpoint
Most important, ket outcome Main research question (hypothesis) of study
Describe a secondary/tertiary/etc.. outcome/endpoint
Lesser importance yet still valuable Possible for future hypothesis generation
Describe a composite outcome/endpoint
Combines multiple endpoints into a single outcome Could be considered the primary outcome, and if so, then secondary outcome may be the individual outcome elements from composite
Examples of Patient-Oriented Endpoints (most clinically relevant)
Death Stroke or Myocardial Infarction Hospitalization Preventing need for dialysis
Examples of 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 of renal function)
Explain Non-Random sample selection and group allocation
Subjects DO NOT have an equal probability of being selected or assigned to each intervention group (e.g., Convenience Sampling, Non-probabilistic allocation)
Explain Random sample selection and group allocation
Most commonly utilized
Subjects 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 (confounders)
In randomization, documentation of equality of groups (effectiveness of randomization process) is reported in 1-of-several locales:
p value shown in table-format
p values not shown, text statement given in table
p values not shown, text statement in article
Describe a Simple Randomization Process
Equal probability for allocation within one of the study groups
Describe a Blocked Randomization Process
Ensures balance within each intervention group
When researchers want to assure all groups are equal in size
Requires someone outside of the study to be in charge of randomization process
Describe a Stratified Randomization Process
Ensures balance with known confounding variable (gender, age, comorbidities)
Can also pre-select levels to be balanced within each interfering factor (confounder)
Describe a Single-Blind Masking Study
Study subjects are not informed which intervention they are receiving
BUT Clinicians/Researchers are
Describe Double-Blind Masking Study
Neither investigators nor study subjects are informed which intervention each subject is receiving
Describe an Open-Label Masking Study
Everyone knows which intervention each subject is receiving
What can be used to assess the adequacy of blinding?
Post-hoc surveys
Define Placebo
Inert treatments made to look identical in all aspects to the active treatments
(Doasage form, dosing frequency, monitoring, therapy requirements)
Define Double-Dummy
More than 1 placebo used
Define Placebo-effect
Improvement in condition; by power of suggestion & due to the care being provided
Can be as large as 30-50%
Define Harthorne Effect
Desire of study subject to “please” investigatiors for reporting positive results (improvement), regardless of treatment allocation
Describe Post-hoc sub-group analysis
Not accepted as appropriate, by most, when not prospectively
“Data-dredging” or “Fishing”
Reduced Power & Increases risk of Type 2 error
What are the ways to manage drop-outs/lost-to-follow-ups?
Include them anyway: Intent-to-treat
Ignore them: per-protocol/efficacy-analysis
Treat them “as treated”
Intent-to-treat results in the following:
Preserves randomization process
Preserves baseline characteristics & group balance at baseline which controls for known and unknown confounders
Maintains statistical power (original sample size)
Describe Pre-protocol or efficacy-analysis
Compliance must be pre-defined
Customarily set at 80-90% compliance with study protocol
Describe As-Treated
Ignores group assignments
Allows subjects to switch groups & be evaluated in group they moved to, end in, or stay in most
Per-Protocol results in the following:
Biases estimates of effect (commonly over-estimates effects)
Reduces generalizability
List ways to Assess Adherence (Compliance)
Drug levels (multiple useful sites)
Pill counts at each visit
Bottle counter-tops
List Methods of Improving Adherence (Compliance)
Frequent follow-up visits/communications
Treatment alarms/notifications
Medication blister packs or dosage containers
