16-19 Interventional Study Designs

Question 1

List the other terms used for interventional studies.

Answer 1

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

Question 2

What is the key difference between observational and interventional studies?

Answer 2

• Investigator selects “interventions” and allocates study subjects to forced-intervention groups
• More “rigorous” in ability to show cause-and-effect
o Can demonstrate causation

Question 3

List and describe the phases of interventional studies.

Answer 3

PRE-CLINICAL (prior to human investigation)
o Bench and animal research
PHASE 1 (new drug/device/procedure)
o Small N (~20-80), healthy volunteers tor used for the first time in humans to assess safety/toxicity, dosing and even pharmacokinetics in population of interest (diseased)
- Short duration (e.g., usually just a few days or weeks or a couple of months)
PHASE 2 (new drug/device/procedure, indication or study population)
o Larger N, (~100-300), commonly utilize patients with condition of interest, used to expand on purpose of Phase 1 study (safety) but also to begin assessing efficacy in diseased population
 Short-to-medium duration (a few to several months)
 Likely to have a narrower inclusion criteria
PHASE 3 (new drug/device/procedure, indication or study population)
o Even larger N (~1000-3000), used in patients with condition of interest to continue determination of safety, with primary purpose to assess efficacy
 Longer duration (many month to a year (or a few years))
 Superiority vs. Noninferiority vs. Equivalency formats
PHASE 4 (post-marketing)
o Long-term effects (risks and benefits) in a large population of diseased patients (expanded use population (age, ethnic))
 Registries, Survey’s (e.g., FDA’s MedWatch/FAERS/VAERS programs)

Question 4

What are the advantages and disadvantages of interventional studies?

Answer 4

Advantages
• Cause precedes effect (shows Causation)
• Only design used by FDA for “approval” process (on-label)
Disadvantages
• Cost
• Complexity/Time (development/approval/conductance)
• Ethical considerations (Risk vs. Benefit evaluation)
• Generalizability (a.k.a.; External Validity)
o Is study population similar to general population and will methodology and findings be applicable to them?

Question 5

Compare pragmatic versus explanatory studies.

Answer 5

• Explanatory has presubscribed playbook that you must abide by. It is not flexible for real clinical practice. They are so restrictive in who can participate. Typically seen in phases 2 and 3.
• Pragmatic studies are still in the family of interventional studies. Clinically applicable. Less restrictive on inclusion criteria.
o Never use placebo - common sense medicine
o Let in regular people - multiple comorbidities, on multiple meds
o Allow physicians to use own clinical judgement to treat patients
o Lose researcher’s control how physician prescribes medication
o Lose lack of other confounding variables - introduced again
• Many researchers will have an explanatory interventional study from phase 1-3, but may (don’t have to) switch to a pragmatic study in phase 4 for more long term benefits/harm, but also for an increase in external validity for medical application purposes - can more patients use it?; incorporate multiple conditions;

Question 6

What are the 4 types of design?

Answer 6

Simple
Fractional
Cross-over
Parallel

Question 7

Define a simple study.

Answer 7

o	Divides (randomizes) subjects exclusively into > 2 groups
	A single randomization process; no subsequent randomized divisions
o	Commonly used to test a single hypothesis (question) at a time

Question 8

Define a fractional study.

Answer 8

o Divides subjects into > 2 groups and then further additionally sub-divides (randomizes) each of the groups in to > 2 sub-groups
 Numerical representation of number of groups and number of divisions (e.g., 2x2 or 3x3x2)
o Used to test multiple hypotheses at the same time (increases sample size requirement)
 Improves efficiency for answering clinical questions
 Increases study population sample size (due to increase group #)
 Increases complexity (which may be a barrier to recruitment)
 Increases risk of drop outs (due to complexity), and
 May restrict generalizability of results

Question 9

Define a parallel study.

Answer 9

o Groups simultaneously and exclusively managed
o No switching of intervention groups after initial randomization
 All simple and factorial designs are also parallel

Question 10

Define a cross-over study.

Answer 10

o Groups serve as their own control by crossing over from one intervention to another during the study
 Allows for small total “N” (sample size)
• Each patient contributes additional data
o Between and within group comparison possible

Question 11

What are the disadvantages of a cross-over study?

Answer 11

 Only suitable for long-term conditions which are not curable or which treatment provides short-terms relief
 Duration of study for each subject is longer
 Carry-over effects during cross-over (wash-out required; which prolongs study duration)
 Treatment-by-Period interaction
• Differences in effects of treatments during different time periods
 Smaller N requirement only applicable if within-subjects variation less than between-subjects variation
 Complexity in data analysis

Question 12

What is a run in or lead in phase?

Answer 12

o All study subjects blindly given one or more placebos for initial therapy (defined time period) to determine a new base-line of disease (standardization)
 Can assess study protocol compliance
 Can “wash-out” existing medication
• Reduces at least 1 possible common exclusion criteria
 Can determine amount of placebo-effect (new-baseline)

Question 13

What are the different types of outcomes?

Answer 13

Primary
Secondary/Tertiary
Composite
Patient-Oriented Endpoints
Surrogate markers

Question 14

What a composite outcome?

Answer 14

Combines multiple endpoints into a single outcome
 Could be considered the Primary outcome, and if so, then secondary outcomes may be the individual outcome elements from Composite

Question 15

What is a primary outcome?

Answer 15

Most important, key outcome(s)

 Main research question (hypothesis) used for developing/conducting study

Question 16

What is a secondary or tertiary outcome?

Answer 16

o Lesser importance yet still valuable

o Possible for future hypothesis generation

Question 17

List some examples of Patient-Oriented Endpoints.

Answer 17

o Death
o Stroke or myocardial infarction
o Hospitalization
o Preventing need for dialysis

Question 18

List some examples of surrogate markers.

Answer 18

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

Question 19

What are the types of Sample Selection & Group Allocation?

Answer 19

Non-Random
Random
Masking

Question 20

What is non-random group allocation?

Answer 20

Subjects don’t have an equal probability of being selected or assigned to each intervention group (e.g., Convenience Sampling/Non-probabilistic allocation)
• Patients attending morning clinic assigned to group 1, patients attending afternoon clinic assigned to group 2
• Patients attending clinic on odd days of the month assigned to group 1, patients attending clinic on even days assigned to group 2
• The first 100 patients admitted to the hospital

Question 21

What is random group allocation?

Answer 21

Subjects do have an equal probability of being assigned to each intervention group
• Random-number generating programs

Question 22

Why do researchers use randomization?

Answer 22

• Purpose to make groups as equal as possible; based on known and unknown important factors (confounders)
o Attempts to reduce systematic differences (bias) between groups which could impact results/outcomes
o Equality of groups not guaranteed

Question 23

What are the types of randomization?

Answer 23

Simple
Blocked
Stratitfied

Question 24

What is simple randomization?

Answer 24

 Equal probability for allocation within one of the study groups

Question 25

What is blocked randomization?

Answer 25

 Ensures balance within each intervention group

 When researchers want to assure that all groups are equal in size

Question 26

What is stratified randomization?

Answer 26

 Ensures balance with known confounding variable
 Examples: gender, age, disease severity/duration, comorbidities
 Can also pre-select levels to be balance within each interfering factor (confounder)

Question 27

List and define the types of masking.

Answer 27

Single
Double
Open Label
Placebo

Question 28

Explain the placebo effect.

Answer 28

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

Question 29

Explain the Hawthorne effect.

Answer 29

o Desire of study subject to “please” investigators by reporting positive results (improvement), regardless of treatment allocation

Question 30

List your options in managing drop outs/lost to follow ups and explain their differences.

Answer 30

Include them
 Last known assessment (observation) used for (carried forward) all subsequent, yet missed assessments (LOCF)
 Convert all subsequent yet missed assessment for a subject to a null-effect (no benefit)
Ignore them
 (include only compliant or completing subjects
Treat them as treated
 Ignores group assignments
 Allows subjects to switch groups and be evaluated in group they moved to, end in, or stay in most

Question 31

List some ways of assessing adherence (compliance).

Answer 31

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

Question 32

List some ways to improve compliance.

Answer 32

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