Interventional Studies

Question 1

What are some other terms that can be used for interventional studies?

Answer 1

• Clinical trial
• Clinical study
• Experimental study
• Human study
• Investigational study

Question 2

Key difference between interventional and observational studies

Answer 2

• Can show causation

- investigator selects interventions and allocates study subjects to forced intervention groups

Question 3

What are the different aspects that determine the different phases of interventional studies?

Answer 3

• Purpose/Focus
• Population studied (healthy/diseased)
• Sample size
• Duration

Question 4

What does the duration of the study depend on?

Answer 4

• the disease or the research question being asked

Question 5

What is the purpose of the pre-clinical stage?

Answer 5

• helps drive the hypothesis

Question 6

Phase 0

Answer 6

• Asses drug-target actions and pharmacokinetics in non-therapeutic/non-diagnostic doses
• Healthy volunteers (or cancer patients)
• Very small (<20)
• Very short duration (single dose to a few days)

Question 7

Phase 1

Answer 7

• Asses safety/tolerance and pharmacokinetics of one or more dosages
• Healthy or disease volunteers (depending on disease)
• Small (20-80)
• Short duration (a few weeks)

Question 8

What are some aspects of pharmacokinetics?

Answer 8

• Absorption
• Distribution
• Metabolism
• Excretion

Question 9

Phase 2

Answer 9

• Asses effectiveness (while still looking at safety and tolerability)
• Diseased volunteers
• Larger N (100-300)
• Short to medium duration (few weeks to a few months)

Question 10

Phase 3

Answer 10

• asses effectiveness (safety and tolerability as well)
• diseased volunteers
  Uses the different perspectives
• Larger N (300-500)
• Longer duration (few months to a year)

Question 11

Phase 4

Answer 11

• post FDA approval
• Assess long term safety, effectiveness and optimal use (risks/benefits)
• Diseased volunteers (comorbidities)
• population N (100,000 - millions)
• Longer duration (many years to decades)

Question 12

Advantages of Interventional Trials

Answer 12

• Cause precedes effect (can demonstrate causation)

- Only design-family used for FDA approval process

Question 13

Disadvantages of Interventional Trials

Answer 13

• Cost
• Complexity/Time
• Ethical considerations
• Generalizability

Question 14

Simple Interventional studies

Answer 14

• Divides (randomizes) subjects once

- Tests a single hypothesis at a time

Question 15

Factorial Interventional Studies

Answer 15

• Divides (randomized) into groups and then further sub-divides each of the groups into additional sub-groups
• Used to test multiple hypotheses at the same time

Question 16

What are some characteristics of factorial interventional studies?

Answer 16

• Improves efficiency for answering clinical questions
• Increases study population sample size
• Increases complexity (which may be a recruitment barrier)
• Increases risk of drop outs
• May restrict generalizability results

Question 17

Parallel Interventional Studies

Answer 17

• groups simultaneously and exclusively manages
• no switching of intervention groups after initial randomization
• All simple and factorial study designs are also parallel

Question 18

Cross-Over (Self-Control) Interventional Studies

Answer 18

• Groups serve as their own control by crossing over from one intervention to another during the study
• Allows for smaller sample size

Question 19

What is a washout period?

Answer 19

Refers to the break that happens after a certain time frame in a crossover study. Before the groups are switched.

Question 20

Run-In/ Lead-in Phase

Answer 20

• determining a new baseline
• cleaning out and baseline establishment before a study starts

Can also be a practice and dry run before the actual study

Question 21

Disadvantages of Cross-Over Design

Answer 21

• only suitable for long term conditions that are not curable or which treatment provides short term relief
• Duration of study for each subject is longer
• Carry-over effects during crossover
• Treatment-by-period interaction
• Smaller N requirement only applicable if within-subjects variation less than between-subjects variation
• Complexity in data analysis

Question 22

Primary Outcome

Answer 22

• Most important, key outcome

- Main research question for developing/conducting study

Question 23

Secondary/Tertiary etc. Endpoints

Answer 23

• Lesser importance but still valuable
• Possible for future hypothesis generation

E.g. Side Effects

Question 24

Composite Endpoints

Answer 24

• Combines multiple endpoint into a single outcome

Can also be called group outcome

Question 25

Examples of Patient oriented Endpoints

Answer 25

- Death - Stroke or MI - Hospitalization - Preventing need for dialysis

Question 26

Examples of disease-oriented endpoints

Answer 26

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

Question 27

Non-Random Sample Selection & Group Allocation

Answer 27

Subjects don't have an equal probability of being selected or assigned to each intervention group

Question 28

Random Sample Selection and Group Allocation

Answer 28

Subject do have an equal probability of being assigned to each intervention group

Question 29

What is the purpose of randomization?

Answer 29

- to make groups as equal as possible; based on known and unknown important factors. - Equality of groups in not guaranteed

Question 30

Forms of Randomization

Answer 30

- Simple - Blocked - Stratified

Question 31

Simple Randomization

Answer 31

- Equal probability for allocation within one of the study groups

Question 32

Blocked Randomization

Answer 32

Ensures balance within each intervention group.

Question 33

Stratified Randomization

Answer 33

Ensure balance with known confounding variables - gender, age, disease etc - can preselect levels to be balance within each interfering factor

Question 34

Types of Masking

Answer 34

- Single-blind - Double-blind - Open-Label (unmasked/unblinded)

Question 35

Single-blind

Answer 35

Subjects not informed but researchers are

Question 36

Double blind

Answer 36

Neither the subject nor the researcher knows which groups the subjects are in

Question 37

Open-Label

Answer 37

Study subjects and researcher both know which intervention is being received

Question 38

Forms of Blinding (Masking)

Answer 38

- Placebo (dummy therapy) - Placebo-effect - Hawthorne effect

Question 39

Placebo

Answer 39

- Inert treatments made to look identical to active treatments

Question 40

Placebo Effect

Answer 40

Improvement in condition by power of suggestion of being treated

Question 41

Hawthorne Effect

Answer 41

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

Question 42

Post-hoc sub-group analysis

Answer 42

- Not accepted as appropriate, by most, when not planned before

Question 43

Intention to Treat

Answer 43

Uses the last know assessment carried forward when a patient is lost to follow-up Also can use the baseline moving forward

Question 44

What does intention-to-treat result in?

Answer 44

- preserves randomization process - preserves baseline characteristics and group balance at baseline which controls for known and unknown confounders - maintains. Statistical power

Question 45

How can you manage drop-outs and lost-to-follow-ups?

Answer 45

- Ignore them - include only those that complied | - Treating them as treated - if they happen to be on the drug that you are looking at you use those results

Question 46

Assessing Adherence (compliance)

Answer 46

- Drug levels (multiple useful sites) - Pill counts at each visit - Bottle counter-tops

Question 47

Methods of Improving Adherence (Compliance)

Answer 47

- Frequent follow-up visits/Communications - Treatment alarms/notifications - Medication blister packs or dosage containers