Interventional Study Designs

Question 1

What is the key difference b/w interventional & observational studies?

Answer 1

Investigator selects interventions and allocates study subjects to forced-intervention groups -can demonstrate Causation

Question 2

What are the two buzz words for interventional study designs?

Answer 2

Randomization and phase

Question 3

Which of the interventional studies has the highest evidence? And lowest evidence?

Answer 3

-Phase 4 (highest) -Phase 0 (lowest)

Question 4

What is a phase 0 study?

Answer 4

(Exploratory, Investigational New Drug)

• First in human use/study ***
• Purpose: asses drug target actions, pharmokinetics a (is drug targeting what its supposed to and at what %)
• It’s to ask a question (not about drug efficacy)
  ex) New Ca therapy, not trying to see if its effective, just if it can get to target
• Healthy volunteers (or dz patients)

-Very small N (<20)

-Very short duration

– usually a single dose to just a few days (max)

Question 5

Phase 1

Answer 5

(Investigational new drug)

-Asses safety/tolerance and pharmokinetics

-Healthy or Dz pats

-Small N (20-80..bigger than phase 0)

-Short duration (several days-few weeks.. longer than phase 0)

• can ppl tolerate drug?
• is it safe?
• Side effects?
• how long does it stay in system?

Question 6

Phase 2

Answer 6

• Asses effectiveness (expands on phase 1)
• Dz volunteers (ppl with condition of interest)

-Larger N (few to several)

-Short to medium duration (several weeks - to several/few months) **

• restrictive inclusion and exclusion criteria
• ex) 128 volunteers with parkinson’s were randomly assigned into 3 groups

Question 7

A one year long study would NOT be which phase studies?

Answer 7

0 or 1

Question 8

Phase 3

Answer 8

***assess effectiveness (continue to asses safety and tolerability)

• diseased volunteers

- larger N (several hundred to few thousand)

- longer duration (few months to a year +) ***

• longer and more ppl than phase 2***
• can be a repeated study, or progression

Question 9

Which phases are healthy patients never used in??

Answer 9

Phase 2, 3, (and 4)

Question 10

When are 2 placebos used?

Answer 10

When the route of administration is different (iv vs inhalation)

Question 11

What is the final phase before they must seek approval from FDA?

Answer 11

Phase 3

Question 12

Phase 4

Answer 12

(post FDA approval)

• assess long-term safety, effectiveness, and optimal use (risks/benefits)
• Dz volunteers (expand use criteria - use more blended popln)
• Population N = few hundred to tens of thousands)
• Wide range of durations (many months to several years, ongoing)
• interventional or observational designs
• track data base of observations

Question 13

What are the advantages and disadvantages of Interventional trials?

Answer 13

Advantages = demonstrate causation and Key designs used by FDA for approval, environment highly controlled.

Diasdav = expensive, complex, timely, ethical considerations, generalizability–external validity

Question 14

Traditional - Exploratory Interventional Studies

Answer 14

• Trying to asses drug effectiveness, optimal use, does it get to the target
• No flexibility for clinicians
• so Pts either live with the terms or drop out -worry about generalizability

Question 15

Pragmatic - Explanatory Interventional Studies

Answer 15

• Still trying to explore most effective tx BUT their goal is how to manage a condition
• gives clinicians more flexibility
• maximized applicability of the trials and results to usual care settings
• more practical management

Question 16

What is the primary difference b/w simple and factorial interventional studies

Answer 16

Simple - only one randomization event

– tests single hypothesis

Factorial - multiple randomization events (2 or more)

– 2x2 or 2x2x2

–multiple hypotheses

Question 17

What is the primary difference b/w parallel and crossover studies?

Answer 17

Parallel = no switching b/w intervention groups

Crossover (self-control) = switching/crossover b/w groups

• advantages of crossover:

– groups can act as their own contorl

– allows for smaller N bc each pt counts as two ppl

– allows b/w and w/in group comparison possible

Question 18

When does wash out occur and what does that mean?

Answer 18

• during crossover studies, can “wash out” previous medicaiton givcen before crossing over
• occurs after the study has already started, so in the middle of the study
• when doing crossover study, it prevents the “hangover effect” and gives times for drug/tx to get out of system

***back to baseline***

Question 19

What does Lead-in mean?And when does it occur?

Answer 19

Lead-in occurs before study starts -asses study protocol compliance (dry run/rhersal) -can act as a washing out phase -can determine amount of placebo effect - can decrease exclusion criteria

Question 20

What are the most CLINICALLY relevant endpoints for interventional studies?

Answer 20

1) Patient-oriented (Patient-Oriented Endpoints = POEM’s)

***happen to people***

• death, stroke/MI, hospitalization, preventing need for dialysis
• pt’s would rather hear they have a decreased risk for death or the above things, than hearing “you lowered my BP # or cholesterol”
  2) DOEMs
• BP, Cholesterol, lab values
• can be used to help predict POEMs but are measures to evaluate whats happening

Question 21

What are some examples of Dz-oriented Endpoints (DOE’Ms)?

Answer 21

• BP
• cholesterol
• change in SCr
• surrogate markers
• used in place of evaluating POEMs

Question 22

What is the goal/purpose of randomization?

Answer 22

To make sure groups are as equal as possible, based on confounders

• decreases biases
• allows group allocation to be taken out of researchers hands

Question 23

What are 3 forms of randomization?

Answer 23

Simple

Blocked

Stratified

Question 24

Describe simple randomization:

Answer 24

equal probability for allocation

Question 25

Describe blocked randomization:

Answer 25

Ensures balance w/in each intervention group

• more hands on
• ex = every N^th person stop and look if groups are even, if unbalanced then put the next ppl where needed

Question 26

Describe stratified randomization:

Answer 26

ensures balance with known confounding variables

• stratified individualistic on particular strata
• gender, age, dz severity etc
• can pre-select levels to be balanced within each confounder

Question 27

What are the 3 types of Masking?

Answer 27

Single-blind

Double-blind

Open-Label (unmasked/unblinded)

Question 28

What is the main difference b/w single and double blind studies?

Answer 28

Single: subject not informed which tx group they’re in, but researcher knows

Double: neither subject or researcher knows -prevents interviewer, response bias

Question 29

What is open-label masking?

Answer 29

Subjects and researcher both know what intervention is being used

• can be a continuation of a double blind study in an open fashion to see if benefit continues

Question 30

What kind of studies can be used to assess the adequacy of blinding?

Answer 30

Post-hoc survey’s

Question 31

What is another name for “Dummy” therapy?

Answer 31

Placebo therapy

• inert tx’s made to look ID in all aspects to the active tx

– dosage forms, dosing frequency, monitoring, therapy requirements

Question 32

What are Double-Dummy tx’s?

Answer 32

Using more than one placebo

– primarily if there are different modes of tx (ex = inhalation vs injection)

Question 33

What is the placebo effect?

Answer 33

Improvement in condition by power of suggestion of being ‘treated’

• can be as large as 30-50%
• benefit just from being in study and getting tx “tender, love and care”

Question 34

Hawthorne-effect

Answer 34

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

Question 35

What are post-hoc sub-group analyses? What are the positives and negatives?

Answer 35

• another analysis after study has been completed and data has already been collected (data-dredging or fishing)

***They are not accepted as appropriate by most when NOT prospectively planned***

• Negatives: reduces power and increases risk of Type 2 error

***Are accepted when prospectively planned and delineated in the methods that it will occur***

-Positives: can allow for hypothesis generation and development of future studies

Question 36

What are the two ways to handle data collected from subjects who dropped out or were lost to f/u?

Answer 36

• Include them anyway
• Ignore them

Question 37

If USE data even if subject dropped out what type of principle is this?

What are the benefits?

Answer 37

Intention to Treat

• Most CONSERVATIVE
• maintains group allocation and preserves randomization
• preserves baseline characteristic and group balance at baseline (which contrls for confounders)
• maintains statistical power

Question 38

What are the 2 most common forms of group allocation procedures?

Answer 38

1) non-random = subjects don’t have equal probability of being selected or assigned to each group
2) random = most used
- subjects DO have equal chance of being assigned to each group

Question 39

When managing Drop outs/ LTFU, you just IGNORE them (including only compliant or completing subjects), what types of studies are these? (theres 2)

Answer 39

1) Per-protocol/Efficacy analysis = compliance is pre-determined
- introduces bias (bc commonly over estimates effects) and decreases generalizability
2) Treating them As treated = ignore original group assignment and count them wherever they fit best
- use data as they were tx not as their intended randomized group
- not common and can introduce contamination bias

Question 40

What are some was to 1) assess adherence/compliance and 2) imoprove adherence?

Answer 40

1) drug levels, pill counts at each visit, bottle counter-tops

*** stay engaged with patients***

2) frequent f/u appointments, communication with subjects, tx alarms/notifications, medication dosage containers