Lecture #7-9 - Interventional Studies

Question 1

Definition: All individuals making up a common group; from which a
sample (smaller set) can be obtained, if desired

Answer 1

Population

Question 2

Definition:A subset or portion of the full, complete population

(“representatives”)

Answer 2

Sample

Question 3

Null Hypothesis (H0)

Answer 3

o A researcher‐perspective which states there is no (true)
difference between the groups being compared
Most conservative and commonly utilized

Question 4

Alternative Hypothesis (H1)

Answer 4

Opposite of the Null Hypothesis – A study hypothesis
(researcher‐perspective) which states there is a (true)
difference between the groups being compared

Question 5

In interventional studies are exposures assigned or not assigned?

Answer 5

assigned

Question 6

The following terms all are another name for:

Clinical Trial, Clinical Study,
Experimental Study, Human Study, Investigational
Study

Answer 6

Interventional Study

Question 7

What is the key difference between observational studies and interventional studies?

Answer 7

In interventional studies the investigator selects interventions and allocates study subjects to forced intervention groups.

Interventional can show causation, observational cannot

Question 8

The following describes which state of Interventional Studies:

prior‐to human investigation

Answer 8

Pre-clinical

Question 9

The following describes which stage of interventional studies:

Small N (~20‐80), healthy volunteers, used for the first time in
humans to assess safety, toxicity and pharmacokinetics

SHORT DURATION

Answer 9

Phase 1

Question 10

The following describes which stage of Interventional Studies:

Larger N (~100‐300), commonly utilize patients with condition
of interest, used to expand on purpose of the earlier phase
(safety) but also to begin assessing efficacy in diseased
population

Answer 10

Phase 2

Question 11

Which stage is likely to have a narrower inclusion criteria?

Phase 1 or Phase 2

Answer 11

Phase 2

Question 12

The following describes which stage of Interventional Studies:

Even Larger N (~1,000‐3,000), used in patients with condition
of interest to continue determination of safety, with primary
purpose to assess efficacy

Long duration (months to years)

Answer 12

Phase 3

Question 13

The following describes which stage of Interventional Study:

Long‐term effects (risks & benefits) in a large population of
diseased patients (expanded use population (age, ethnic))

Post-marketing

Answer 13

Phase 4

Question 14

What are the disadvantages of Interventional Trials (state 2 - there are 4)

Answer 14

o Cost
o Complexity/Time (development/approval/conductance)
o Ethical considerations (Risk vs. Benefit evaluation)
o Generalizability (a.k.a.; External Validity) – Is study
population similar to general population and will
methodology and findings be applicable to them?

Question 15

Which design of interventional studies divides groups into 2 or more groups and includes only one randomization process. This is typically used to test a single hypothesis.

Answer 15

Simple

Question 16

Which design of interventional studies divides the subjects into two or more groups AND ALSO additionaly subdivides each of the groups into two or more groups

Answer 16

Factorial

(3x3x2 etc)

Question 17

What are the properties of a Factorial type design?

Answer 17

• Improves efficiency for answering clinical questions
• Increases study population sample size (due to increased 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 18

What type of study design has groups simultaneously and exclusively managed
with no switching of intervention groups after initial randomization

Answer 18

Parallel

• All Simple and Factorial study designs are also Parallel

Question 19

What type of study design has Groups serve as their own control by crossing over from one intervention to another during the study

Answer 19

Cross-over (aka Self-control)

• Allows for smaller total “N” (sample size)
• Each patient contributes additional data

Question 20

What are TWO disadvantages of cross-over design?

Answer 20

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

Question 21

What is the difference between a “wash-out” and “lead-in” phase?

Answer 21

lead in is before the trial. Wash-out is in the middle and normally as one group is crossing over to test a different variable.

Question 22

Define the following referring to Outcomes/Endpoints:

• Primary
• Secondary / Tertiary / etc…
• Composite

Answer 22

o Primary- Most important, key outcome(s)
• Main research question (hypothesis) used for developing/conducting
study

o Secondary / Tertiary / etc…
Lesser importance yet still valuable
Possible for future hypothesis generation

o Composite - Combines multiple endpoints into a single outcome

Question 23

The following are examples of what kind of Endpoints?

 Death
 Stroke or Myocardial infarction
 Hospitalization
 Preventing need for dialysis

Answer 23

Direct Endpoints

Question 24

What would you describe the following as (elemends used in palce of evaluating direct endpoints)

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

Answer 24

Surrogate Markers

Question 25

Define Non-random group allocation:

Answer 25

Subjects don’t have an equal probability of being selected or assigned to each intervention group (e.g., Convenience Sampling/Non‐probabilistic allocation) example: first 100 patients admitted to a hospital

Question 26

Define Random group allocation:

Answer 26

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

Question 27

What is the purpose of randomization? Where would you find information on randomization in a paper? Is equality guaranteed?

Answer 27

to make groups as equal as possible; based on known and unknown important factors (confounders) Table 1 No

Question 28

Which form of randomization Ensures balance within each intervention group to ensure all groups are equal in size

Answer 28

Blocked

Question 29

Which form of randomization Ensures balance with known confounding variables like age, gender, disease severity?

Answer 29

Stratified

Question 30

The following refers to what type of masking? Study subjects are not informed which intervention they are receiving (but clinicians/researchers are!)

Answer 30

Single‐Blind

Question 31

The following refers to what type of masking? Neither investigators nor study subjects are informed which intervention each subject is receiving

Answer 31

Double‐Blind

Question 32

The following refer to what type of masking? Everyone knows which intervention each subject is receiving

Answer 32

Open‐Label

Question 33

How could you assess the adequacy of blinding?

Answer 33

post-hoc surveys

Question 34

Placebo (“Dummy” therapy) refers to:

Answer 34

Inert treatments made to look identical in all aspects to the active treatments Double‐Dummy – more than 1 placebo used

Question 35

What is the Placebo effect?

Answer 35

Improvement in condition; by power of suggestion & due to the care being provided Can be as large as 30‐50%!

Question 36

What is the Hawthorne‐effect

Answer 36

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

Question 37

Discuss: o Inclusion/Exclusion criteria (interventional studies) & Case‐ and Exposure‐defined (observational studies)  Desired vs. Logical vs. Plausible  These absolutely impact generalizability! • External Validity

Question 38

Define: Autonomy

Answer 38

Self‐rule/Self‐determination. Participants must… • Have full & complete understanding of the risks and benefits * No misinformation, incomplete information, or ineffectively‐conveyed information (language or education level) * Decide for ones‐self, without outside influences * No coercion, reprisal, financial manipulation

Question 39

Define: Beneficence

Answer 39

To benefit, or do good for, the patient (not society)

Question 40

Define Justice in regards to bioethics

Answer 40

Equal & Fair treatment regardless of patient characteristics

Question 41

Define **Nonmaleficence** with regard to Bioethics

Answer 41

 Do no harm. Researchers must not… • Withhold information • Provide false information • Exhibit professional incompetence

Question 42

What is the difference between consent and assent?

Answer 42

Consent:Agreement to participate, based on being fully and completely informed [given by mentally‐capable individuals of legal consenting age (i.e., adults; age 18 in most states)] **(FOR CHILDREN)** Assent: Agreement to participate, based on being fully and completely informed, given by mentally‐capable individuals not able to give legal consent (i.e., children and adolescents)

Question 43

1978; issued by National Commission for Protection of Human Subjects of Biomedical and Behavioral Research

Answer 43

Belmont Report The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations.

Question 44

What is the role of the IRB? What type of studies MUST be reviewed?

Answer 44

to protect human subjects from undue risk (not complying with principles of bioethics) All human subject studies MUST be reviewed by an IRB prior to study initiation

Question 45

# Define: Equipoise

Answer 45

genuine confidence that an intervention may be worthwhile (risk vs. benefit) in order to use it in humans

Question 46

What officer enforces the regulations of the IRB? What officers develops regulations for the IRB?

Answer 46

Office of Human Research Protections (OHRP) Department of Healthand Human Services (DHHS)

Question 47

Which level of IRB: – used for ALL interventional trials with more than minimal/no risk to patients  All medication‐related studies

Answer 47

Full Board

Question 48

Which level of IRB: has minimal risk and no patient identifiers

Answer 48

Expedited

Question 49

Which level of IRB: has no patient identifiers, low/no risk, de‐ identified dataset analysis, environmental studies, use of existing data/specimens (de‐identified)

Answer 49

Exempt

Question 50

Do studies that qualify for exempt level of IRB have to be submitted at all?

Answer 50

YES

Question 51

WHO gets to decide level of review?

Answer 51

The IRB

Question 52

What does the Data Safety & Monitoring Board (DSMB) do?

Answer 52

Semi‐Independent committee not involved with the conduct of the study but charged with reviewing study data as study progresses, to assess for undue risk or benefit

Question 53

When managing drop outs/ LTFs: Intent‐to‐Treat (most conservative decision) involves..

Answer 53

• Last known assessment (observation) used for (carried forward) all subsequent, yet missed assessments (LOCF) • Convert all subsequent yet missed assessments for a subject to a null‐effect (no benefit)

Question 54

Intent‐to‐Treat results in what?

Answer 54

 Preserves randomization process  Preserves baseline characteristics and group balance at baseline which controls for known and unknown confounders  Maintains statistical power (original sample size)

Question 55

If a patient wants to / have to switch groups, this would be defined as:

Answer 55

o Treating 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 56

The third option other than as treated and intent-to-treat would be:

Answer 56

to ignore themm (include only compliant or completing subjects)

Question 57

What are ways you could assess adherence (compliance)?

Answer 57

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

Question 58

What are some ways you could improve adherence (compliance)?

Answer 58

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

Question 59

CHEST GUIDELINES? Do we need to know?