Interventional Study Designs

Question 1

Explain where Interventional (exploratory) and pragmatic (explanatory) studies are in the research evidence pyramid and why they are ranked so highly.

Answer 1

They are both found at the same level, 2nd from the top of the pyramid

both of these study types control the exposure so tightly, that any change in outcome that we see must be very likely to be due to the controlled exposure

Question 2

What is the main difference of Interventional studies when compared to observational studies? what is useful about this difference?

Answer 2

the investigator selects “interventions” AND allocates study subjects to forced-intervention groups

this more “rigorous” design allows interventional studies to demonstrate causation

Question 3

List the 4 general differentiators of interventional studies.

Answer 3

1. Purpose of the study
2. The population being studied (healthy/diseased)
3. Sample Size
4. Duration of the study/observation

Question 4

describe Phase 0 interventional studies in terms of “purpose, population, sample size, and duration”

Answer 4

1. assess drug-target interactions and possibly pharmacokinetics “does this drug do what we thought it would do?”
2. Healthy or diseased volunteers
3. very small SS (<20 and usually <12)
4. very short duration (single dose to a few days)

Phase 0 are exploratory (used to investigate new drugs)p

Question 5

Describe interventional study designs

Answer 5

forced allocation into groups occurs, and randomization is usually used to accomplish this. Able to prove causation but can be less ethical

Question 6

Describe observational study designs

Answer 6

researchers observe subjects occurring naturally or subjects that freely agree to be observed in a study. Cannot prove causation, and there is NO forced group allocation

Question 7

state, in increasing order of level of evidence, the Inerventional and observational study design types (5 each)

Answer 7

Interventional: Phase 0 through phase 4

Observational: Case reports/series, Ecological, Cross sectional, case-control, and cohort

Question 8

Describe Preclinical interventional clinical trials

Answer 8

(prior to human investigation) “bench” or animal research

Question 9

Describe phase 0 interventional clinical trials in terms of they type of study, the main aspect of the exposure being studied, the type of subjects, the sample size, and the length of the study.

Answer 9

Exploratory

assesses drug-target actions/pharmacokinetics in single or few doses (first human testing)

Healthy (sometimes diseased) volunteers

Small N (less than 20)

Short duration

Question 10

Describe phase 1 interventional clinical trials in terms of they type of study, the main aspect of the exposure being studied, the type of subjects, the sample size, and the length of the study.

Answer 10

Investigational (NOT testing effectiveness yet)

Assess safety/tolerance (all tests after this test safety too) and pharmacokinetics in a “few doses”

Healthy or diseased volunteers

Small N (20-80)

Short duration (a few weeks)

Question 11

Describe phase 2 interventional clinical trials in terms of they type of study, the main aspect of the exposure being studied, the type of subjects, the sample size, and the length of the study.

Answer 11

Investigational

Assess effectiveness of drug

Diseased volunteers only (may narrow inclusion criteria for this phase)

Larger N (100-300)

Short-to-Medium duration (few weeks/months)

Question 12

Describe phase 3 interventional clinical trials in terms of they type of study, the main aspect of the exposure being studied, the type of subjects, the sample size, and the length of the study.

Answer 12

Investigational (Indication/Population) last phase before FDA approval

Assess effectiveness, safety and tolerability

Diseased volunteers (may expand inclusion criteria and comparison groups for a delineation of effect)

Statistical perspectives are taken here (superior/noninferiority/equivalency)

Larger N (500-3000)

Longer duration (few months to a year or more)

Question 13

Describe phase 4 interventional clinical trials in terms of they type of study, the main aspect of the exposure being studied, the type of subjects, the sample size, and the length of the study.

Answer 13

Post-FDA approval

Assess long-term safety/effectiveness and optimal use (risk/benefits)

Diseased volunteers (expands use criteria to delineate long-term saftey/effects)

Population N (few hundred to few thousand)

Wide-range of durations (depends on the drug being tested)

Question 14

What are the advantages of interventional clinical trials?

Answer 14

The cause precedes the effect and therefore demonstrates causation

These are the only study designs that the FDA uses to “approve” of drugs

Question 15

What are the disadvantages of interventional clinical trials?

Answer 15

Costly, complex, and time consuming

Ethically questionable issues may arise

Generalizability/external validity is brought into question (how applicable is this data to the real world?)

Question 16

Explain why interventional clinical trials can prove causation

Answer 16

The cause precedes the effect, and can therefore proves causation? And the study environment is also controlled by this study (so all other exposures/environtment are controlled for as well)

Question 17

Describe and give an example of Simple study design. also list and advantage and disadvantage of this study design type

Answer 17

randomly divides subjects exclusively into no more than 2 groups and is commonly used to test a single hypothesis ex. One placebo group and one treatment group

Advantages: simple

Disadvantages: only tests one question at a time

Question 18

Describe and give an example of Parallel study design. also list an advantage and disadvantage of this study design type

Answer 18

NO switching occurs after the initial randomization occurs ex. All simple and factorial designs are also parallel

Advantages: there cannot be confounders due to exposure to a different drug/treatment, like in cross-over studies and it takes less time to complete

Disadvantages: answers fewer questions than other studies

Question 19

Describe and give an example of Factorial study design. also list an advantage and disadvantage of this study design type

Answer 19

randomly Divides subjects into more than 2 groups and then further divides subjects into more than 2 sub-groups. Used to test multiple hypotheses at once ex. (has several types that are represented by the numerical representation of the groups and sub-groups ex. 2x2, 3x3x2)

Advantages: improves efficiency for answering clinical questions and increases the study population size(out of necessity due to the larger # of groups)

Disadvantages: increases complexity (which may be a barrier to recruitment and increased the risk of drop-outs) and it may restrict the generalizability of the results

Question 20

Describe and give an example of Cross-Over study design. also state an advantage and disadvantage of this study design type

Answer 20

(self control studies) serve as their own control group by “crossing-over” groups once the study has begun.

Advantages: allows for smaller N values because each subject provides more data than in other studies

Disadvantages: time consuming, washout’s can be messed up, and confounding subjects contribute more data and therefore more confounding

Question 21

differentiate between primary, secondary, and composite outcomes

Answer 21

Primary: the most important outcome, which answers the hypothesis that was used to develop/conduct the study

Secondary/Tertiary/etc: Less important than primary outcome, but can be used to form possible future hypothesis by which further studies can be conducted

Composite: Combines multiple endpoints into a single outcome
(this could be considered the primary outcome, and if that is the case then the secondary outcomes may be the individual outcome elements from composite)

Question 22

Compare and contrast patient-oriented endpoints and disease-oriented outcomes. give some examples of both

Answer 22

Patient-Oriented Endpoints (POEM’s): are the most clinically relevant (patients care about these)
Ex. Death, stroke, MI, Hospitalization, and preventing the need for dialysis

Disease-oriented Endpoints (DOE’s): “surrogate outcomes” used in place of evaluating POEM’s
ex. Blood pressure (risk of stroke), Cholesterol (risk for MI), and Change in SCr (risk for worsening renal functioning)

Question 23

What are the 2 most common general forms of group allocation procedures, when conducting an interventional clinical trial. give examples of each.

Answer 23

Nonrandom: subjects DON’T have an equal probability of being assigned to each group.
Ex. Morning clinic subjects and evening clinic subjects represent the 2 groups OR the first 100 patients admitted to the hospital representing a group

Random: Subjects DO have an equal probability of being assigned to each group
ex. Random-number generating programs

Question 24

Define randomization and explain how it can yield variable results

Answer 24

Randomization: any method used to make the probability of landing in a group as EQUAL as possible

Even when randomization is used, the equality of the groups is not guaranteed and could potentially have very unequal results. Studies have to document the equalization of the groups by referencing their p value in some way

Question 25

What are the 3 randomization types that can be utlized by researchers?

Answer 25

simple, blocked, and stratified

Question 26

Describe simple randomization methods

Answer 26

Simple: equal probability for allocation within one of the study groups

Question 27

Describe blocked randomization methods

Answer 27

Blocked: ensures balance between each intervention group (creates groups of equal sizes)

Question 28

Describe stratified randomization methods

Answer 28

Stratified: ensures balance with known confounding variables between groups, and can even pre-select the level of stratification that is desired (not exactly random)

Question 29

Compare and contrast simple and double blind methods

Answer 29

Single-Blind: study subjects do not know which intervention group they are in, but investigators DO know

Double-Blind: Both the subjects and the investigators do not know which intervention group the subjects are in
Post-study surveys are often used to assess exactly how adequate the blinding protocol was

Question 30

Describe Placebo/Dummy treatment when it come’s to it’s associate with conducting an interventional clinical trial study

Answer 30

inert (placebo) treatments are made to look identical in all aspects to the active treatments in dosage form, frequency, monitoring, therapy requirements, and so on

Question 31

Describe Double-Dummy treatment when it come’s to it’s associate with conducting an interventional clinical trial study

Answer 31

more than 1 placebo is used but still given the “dummy treatment”

Question 32

Describe Placebo-effect when it come’s to it’s associate with conducting an interventional clinical trial study

Answer 32

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

Question 33

Describe Hawthorne-effect when it come’s to it’s associate with conducting an interventional clinical trial study

Answer 33

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

Question 34

Describe Run-in/Lead-in phase when it come’s to it’s associate with conducting an interventional clinical trial study

Answer 34

a period of time that occurs BEFORE the study begins and is often used as a “practice” period where researchers can asses the ability of a subject to adhere to the study’s protocols.

Question 35

Describe Wash-out phase when it come’s to it’s associate with conducting an interventional clinical trial study

Answer 35

a period of time that occurs when crossing subjects over into another group that attempts to return them back to baseline values. Occurs AFTER the study begins

Question 36

List ways to assess study participant adherence/compliance in an interventional clinical trial.

Answer 36

Use drug levels so that there are multiple useful sites

Conduct pill counts at each visit

Use the “bottle counter-tops”

Question 37

List ways to improve study participant adherence/compliance in an interventional clinical trial.

Answer 37

Conduct frequent follow-up visits/have good communication methods

Have subjects set treatment alarms/reminders so they don’t forget

Use medication blister packs/dosage containers to help subjects