Classes 16-19 Interventional Study Design

Question 1

What type of study is most commonly read and the only type to prove causation?

Answer 1

Interventional studies

Question 2

Name other terms used for interventional studies

Answer 2

Clinical trial Clinical study Experimental study Human study Investigational study

Question 3

What are the phases of interventional studies?

Answer 3

Pre-Clinical Phase 1 Phase 2 Phase 3 Phase 4

Question 4

What phase is prior-to human investigation and is usually associated with bench and animal research?

Answer 4

Pre-clinical

Question 5

What phase does this describe? Small population (~20-80) Short duration Safety

Answer 5

Phase 1

Question 6

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

Answer 6

Phase 2

Question 7

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

Answer 7

Phase 3

Question 8

What phase does this describe? Long-term effects Risks and Benefits Large population size Registries/Surveys

Answer 8

Phase 4

Question 9

What are the advantages of interventional trials (vs. other designs)?

Answer 9

Cause precedes effect (shows causation) Only design used by FDA for “approval” process

Question 10

What are the disadvantages to interventional studies (vs. other designs)?

Answer 10

Cost Complexity/Time (development/approval/conductance) Ethical considerations (risk vs. benefit eval) **Generalizability (aka External Validity)

Question 11

What are the disadvantage of an “explanatory” interventional study?

Answer 11

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

Question 12

How is a “pragmatic” interventional study less restrictive than an “explanatory” interventional study?

Answer 12

Pragmatic studies rarely use placebo More clinically relevant Let in real people, people that have real co-morbidities, people on other meds

Question 13

What are the disadvantages of “pragmatic” interventional studies?

Answer 13

Researcher loses control of how physicians prescribe/manage patients Might introduce confounding Loss of control and rigidity

Question 14

Describe a SIMPLE study design

Answer 14

Divides subjects into as many as 2 groups (single randomization process) Commonly used to test a SINGLE hypothesis

Question 15

Describe a FACTORIAL study design

Answer 15

Divides subjects into two or more groups and then further randomizes Used to test multiple hypotheses at the same time Must increase population size

Question 16

What are the benefits/disadvantages to a FACTORIAL study design?

Answer 16

Improves efficiency for answering clinical questions Increases study pop. sample size Increases complexity Increases risk of drop outs May restrict generalizability of results

Question 17

Describe a PARALLEL study design

Answer 17

Groups simultaneously and exclusively managed No switching of intervention groups after initial randomization Includes all simple and factorial study designs

Question 18

Describe a CROSS-OVER study design

Answer 18

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

Question 19

Wash-out Phase

Answer 19

Period needed for groups to get their systems back to baseline

Question 20

Define Lead-in/Run-in Phase

Answer 20

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

Question 21

What can we assess/determine from the Lead-in/Run-in phase?

Answer 21

Can assess study protocol compliance Can “wash-out: existing medication Can determine amount of placebo-effect

Question 22

List the disadvantages of cross-over design

Answer 22

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

Question 23

What study format is demonstrated in the graphic?

Answer 23

Simple, Parallel

Question 24

Describe a Primary Outcome/Endpoint

Answer 24

Most important, ket outcome Main research question (hypothesis) of study

Question 25

Describe a secondary/tertiary/etc.. outcome/endpoint

Answer 25

Lesser importance yet still valuable Possible for future hypothesis generation

Question 26

Describe a composite outcome/endpoint

Answer 26

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

Question 27

Examples of Patient-Oriented Endpoints (most clinically relevant)

Answer 27

Death Stroke or Myocardial Infarction Hospitalization Preventing need for dialysis

Question 28

Examples of Surrogate Markers (elements used in place of evaluating Patient-Oriented (direct) Endpoints)

Answer 28

Blood Pressure (for risk of stroke) Cholesterol (for risk of heart attack) Change in SCr (for worsening of renal function)

Question 29

Explain Non-Random sample selection and group allocation

Answer 29

Subjects DO NOT have an equal probability of being selected or assigned to each intervention group (e.g., Convenience Sampling, Non-probabilistic allocation)

Question 30

Explain Random sample selection and group allocation

Answer 30

Most commonly utilized

Subjects DO have an equal probability of being assigned to each intervention group

Question 31

What is the purpose of randomization?

Answer 31

To make groups as equal as possible; based on known and unknown important factors (confounders)

Question 32

In randomization, documentation of equality of groups (effectiveness of randomization process) is reported in 1-of-several locales:

Answer 32

p value shown in table-format

p values not shown, text statement given in table

p values not shown, text statement in article

Question 33

Describe a Simple Randomization Process

Answer 33

Equal probability for allocation within one of the study groups

Question 34

Describe a Blocked Randomization Process

Answer 34

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

Question 35

Describe a Stratified Randomization Process

Answer 35

Ensures balance with known confounding variable (gender, age, comorbidities)

Can also pre-select levels to be balanced within each interfering factor (confounder)

Question 36

Describe a Single-Blind Masking Study

Answer 36

Study subjects are not informed which intervention they are receiving

BUT Clinicians/Researchers are

Question 37

Describe Double-Blind Masking Study

Answer 37

Neither investigators nor study subjects are informed which intervention each subject is receiving

Question 38

Describe an Open-Label Masking Study

Answer 38

Everyone knows which intervention each subject is receiving

Question 39

What can be used to assess the adequacy of blinding?

Answer 39

Post-hoc surveys

Question 40

Define Placebo

Answer 40

Inert treatments made to look identical in all aspects to the active treatments

(Doasage form, dosing frequency, monitoring, therapy requirements)

Question 41

Define Double-Dummy

Answer 41

More than 1 placebo used

Question 42

Define Placebo-effect

Answer 42

Improvement in condition; by power of suggestion & due to the care being provided

Can be as large as 30-50%

Question 43

Define Harthorne Effect

Answer 43

Desire of study subject to “please” investigatiors for reporting positive results (improvement), regardless of treatment allocation

Question 44

Describe Post-hoc sub-group analysis

Answer 44

Not accepted as appropriate, by most, when not prospectively

“Data-dredging” or “Fishing”

Reduced Power & Increases risk of Type 2 error

Question 45

What are the ways to manage drop-outs/lost-to-follow-ups?

Answer 45

Include them anyway: Intent-to-treat

Ignore them: per-protocol/efficacy-analysis

Treat them “as treated”

Question 46

Intent-to-treat results in the following:

Answer 46

Preserves randomization process

Preserves baseline characteristics & group balance at baseline which controls for known and unknown confounders

Maintains statistical power (original sample size)

Question 47

Describe Pre-protocol or efficacy-analysis

Answer 47

Compliance must be pre-defined

Customarily set at 80-90% compliance with study protocol

Question 48

Describe As-Treated

Answer 48

Ignores group assignments

Allows subjects to switch groups & be evaluated in group they moved to, end in, or stay in most

Question 49

Per-Protocol results in the following:

Answer 49

Biases estimates of effect (commonly over-estimates effects)

Reduces generalizability

Question 50

List ways to Assess Adherence (Compliance)

Answer 50

Drug levels (multiple useful sites)

Pill counts at each visit

Bottle counter-tops

Question 51

List Methods of Improving Adherence (Compliance)

Answer 51

Frequent follow-up visits/communications

Treatment alarms/notifications

Medication blister packs or dosage containers