Lecture 8: interventional studies

Question 1

how are interventional studies divided up (in increasing evidence)

Answer 1

phase 0 through phase 4

Question 2

what are the differentiators within each phase?

Answer 2

1. purpose/focus
2. population studied (healthy/diseased)
3. sample size
4. duration

Question 3

pre-clinical

Answer 3

prior to human investigations– bench or animal research

Question 4

phase 0

Answer 4

exploratory; investigational new drug– FIRST human contact

1. assess drug-target actions and possibly pharmacokinetics in single or ‘a few’ doses
2. healthy (or diseased in oncology) volunteers
3. small population (less than 20)
4. short duration (single dose to few days)

Question 5

phase 1

Answer 5

investigational new drug

1. assess safety/tolerance (first in human)
2. healthy OR diseased
3. small pop (20-80)
4. short –> few days to few weeks

Question 6

phase 2

Answer 6

investigational new drug

1. assess effectiveness, continues to assess safety/tolerability
2. diseased
3. 100-300
4. short to medium duration–> few weeks to few months

Question 7

phase 3

Answer 7

investigational new drug–> LAST PHASE before FDA approval

1. assess effectiveness
2. diseased (expanded inclusion criteria & placebo comparison)
3. 500-3000
4. few months to a year
   * *few rounds of this needed

Question 8

phase 4

Answer 8

post FDA approval

1. assess long-term safety, effectiveness, and optimal use
2. diseased volunteers
3. whole population used
4. wide-range of durations (few weeks to several years)
   * **registries and surveys used to track long-term

Question 9

advantages of interventional trials

Answer 9

cause precedes effect–> can demonstrate CAUSATION

only designs used by FDA approval process

Question 10

disadvantages of interventional trials

Answer 10

cost
complexity/time
ethical considerations
generalizability (external validity)

Question 11

exploratory study

Answer 11

answers research question –> EXPLORES research for dosages, etc.

useful? helpful? best dose?

Question 12

explainatory (pragmatic) study

Answer 12

real clinical life
clinicians making decisions: dosages changes, drug switches, etc.
hard to compare at the end

Question 13

interventional study designs (pick one of each)

Answer 13

1. simple OR factorial

2. parallel OR cross-over

Question 14

simple interventional study

Answer 14

only ONE randomization step to divide subjects into groups

tests SINGLE hypothesis at a time

Question 15

factorial interventional study

Answer 15

randomizes subjects into groups TWO OR MORE times
can ask more than one question at a time
ex: drug 1 alone OR drug 1 + 2 combined better??

Question 16

parallel interventional study

Answer 16

groups are simulataneously and exclusively managed; once they’re randomized into groups they STAY there = no cross-over occuring

Question 17

cross-over interventional study

Answer 17

groups serve as their own control by crossing over from one intervention to another during the study

• -allows for smaller study size because you can get double the data from a single person (they try both drugs)
• -DOWNFALL: lasts longer because they’re followed for BOTH drugs and they have washout phase; only suitable for long-term conditions that are not curable; complex data analysis

Question 18

what two phases occur before/during a cross-over interventional study

Answer 18

lead in phase

wash out phase

Question 19

lead in phase

Answer 19

“practice run” with placebo to flush out previously used drugs AND test compliance, adherence, etc.
can determine new baseline

Question 20

wash out phase

Answer 20

period of time where NO drugs are given in order to clear system before next drug is given

Question 21

outcomes/endpoints of interventional studies

Answer 21

primary = most important
secondary, tertiary, etc. = lesser importance, but still valuable
composite = combines multiple endpoints into single outcome

Question 22

patient-oreinted endpoints (POEM’s)

Answer 22

death, stroke, myocardial infarction, hospitalization, preventing need for dialysis

Question 23

disease-oreinted endpoints (DOE’s)

Answer 23

blood pressure (for stroke risk)
cholesterol (for heart attack risk)
change in SCr (for worsening renal function)

Question 24

purpose of randomization

Answer 24

to make groups as equal as possible, based on known and unknown important factors (confounders); attempts to reduce bias between groups

–equality is NOT guarenteed & documentation of equality of groups must be reported

Question 25

types of randomization

Answer 25

simple
blocked
stratified

Question 26

simple randomization

Answer 26

equal probability for allocation within one of the study groups (just normal randomization)

Question 27

blocked randomization

Answer 27

ensures balance within each intervention group; used when researchers want to make sure they’re equal SIZE
–block “checks” can influence where people are put in groups to ensure same numbers in each

Question 28

stratified

Answer 28

ensures balance with known confounding variables

ex: gender, age, disease, comorbidities, etc.

Question 29

types of masking in interventional studies

Answer 29

single-blind
double-blind
open-label
placebo (dummy) therapy

Question 30

single-blind study

Answer 30

study subjects not informed which group they’re in

investigators do know

Question 31

double-blind study

Answer 31

neither investigators nor study subjects are informed which intervention group subjects are in

Question 32

open-label

Answer 32

both study subjects and researchers know what intervention is being received

Question 33

placebo (dummy) therapy

Answer 33

inert treatments made to look identical in all aspects to the active treatments; dosage form, dosing frequency, monitoring, etc.

Question 34

double dummy therapy

Answer 34

more than one placebo used

Question 35

placebo effect

Answer 35

improvement in condition by power of suggestion of being “treated” (can be as large as 30-50%)

Question 36

hawthorne-effect

Answer 36

study subjects change their behavior solely due to awareness of being studied/observed

Question 37

post-hoc sub-group analysis

Answer 37

not accepted as appropriate, by most, when NOT prospectively planned
–“data-dredging” or “fishing”
IS accepted when planned ahead

Question 38

ways to manage drop-outs/lost-to-follow-ups

Answer 38

1. include them anyway: intent to treat
2. ignore them
3. treat them “as treated”

Question 39

intent to treat

Answer 39

• *most conservative decision
• -last known observation is carried forward for all subsequent assessments (LOCF)
• -convert all subsequent yet missed to assessments to a null-effect (no benefit)

Question 40

result of intent-to-treat

Answer 40

preserved randomization process
preserves baseline characteristics and group balance at baseline, which controls for known and unknown confounders
maintains statistical power

Question 41

ignoring drop-outs

Answer 41

including only compliant or completing subjects

• -per protocol or efficacy-analysis
• compliance must be pre-defined

Question 42

treating drop outs “as treated”

Answer 42

ignores group assignments

allows subjects to switch groups and be evaluated in group they moved to, end in, or stayed in most

Question 43

impact of drop out decisions

Answer 43

per-protocal results in biases estimates of effect (commonly over-estimates)
-reduces generalizability

Question 44

how to assess adherence (compliance)

Answer 44

drug levels
pill counts at each visit
bottle counter-tops

Question 45

how to improve adherence (compliance)

Answer 45

frequent follow-up visits/communications
treatment alarms/notifications
medication blister packs or dosage containers