Lecture #7-9 - Interventional Studies Flashcards
Definition: All individuals making up a common group; from which a
sample (smaller set) can be obtained, if desired
Population
Definition:A subset or portion of the full, complete population
(“representatives”)
Sample
Null Hypothesis (H0)
o A researcher‐perspective which states there is no (true)
difference between the groups being compared
Most conservative and commonly utilized
Alternative Hypothesis (H1)
Opposite of the Null Hypothesis – A study hypothesis
(researcher‐perspective) which states there is a (true)
difference between the groups being compared
In interventional studies are exposures assigned or not assigned?
assigned
The following terms all are another name for:
Clinical Trial, Clinical Study,
Experimental Study, Human Study, Investigational
Study
Interventional Study
What is the key difference between observational studies and interventional studies?
In interventional studies the investigator selects interventions and allocates study subjects to forced intervention groups.
Interventional can show causation, observational cannot
The following describes which state of Interventional Studies:
prior‐to human investigation
Pre-clinical
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
Phase 1
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
Phase 2
Which stage is likely to have a narrower inclusion criteria?
Phase 1 or Phase 2
Phase 2
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)
Phase 3
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
Phase 4
What are the disadvantages of Interventional Trials (state 2 - there are 4)
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?
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.
Simple
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
Factorial
(3x3x2 etc)
What are the properties of a Factorial type design?
- 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
What type of study design has groups simultaneously and exclusively managed
with no switching of intervention groups after initial randomization
Parallel
• All Simple and Factorial study designs are also Parallel
What type of study design has Groups serve as their own control by crossing over from one intervention to another during the study
Cross-over (aka Self-control)
- Allows for smaller total “N” (sample size)
- Each patient contributes additional data
What are TWO disadvantages of cross-over design?
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
What is the difference between a “wash-out” and “lead-in” phase?
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.
Define the following referring to Outcomes/Endpoints:
- Primary
- Secondary / Tertiary / etc…
- Composite
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
The following are examples of what kind of Endpoints?
Death
Stroke or Myocardial infarction
Hospitalization
Preventing need for dialysis
Direct Endpoints
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)
Surrogate Markers
Define Non-random group allocation:
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
Define Random group allocation:
Subjects do have an equal probability of being assigned to each intervention group
What is the purpose of randomization?
Where would you find information on randomization in a paper?
Is equality guaranteed?
to make groups as equal as possible; based on
known and unknown important factors (confounders)
Table 1
No
Which form of randomization Ensures balance within each intervention group to ensure all groups are equal in size
Blocked
Which form of randomization Ensures balance with known confounding variables like age, gender, disease severity?
Stratified
The following refers to what type of masking?
Study subjects are not informed which intervention they are
receiving (but clinicians/researchers are!)
Single‐Blind
The following refers to what type of masking?
Neither investigators nor study subjects are informed which
intervention each subject is receiving
Double‐Blind
The following refer to what type of masking?
Everyone knows which intervention each subject is receiving
Open‐Label
How could you assess the adequacy of blinding?
post-hoc surveys
Placebo (“Dummy” therapy) refers to:
Inert treatments made to look identical in all aspects to the active
treatments
Double‐Dummy – more than 1 placebo used
What is the Placebo effect?
Improvement in condition; by power of suggestion & due to the
care being provided
Can be as large as 30‐50%!
What is the Hawthorne‐effect
Desire of study subject to “please” investigators by reporting positive results (improvement), regardless of treatment allocation
Discuss:
o Inclusion/Exclusion criteria (interventional studies) & Case‐
and Exposure‐defined (observational studies)
Desired vs. Logical vs. Plausible
These absolutely impact generalizability!
• External Validity
Define: Autonomy
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
Define: Beneficence
To benefit, or do good for, the patient (not society)
Define Justice in regards to bioethics
Equal & Fair treatment regardless of patient characteristics
Define Nonmaleficence with regard to Bioethics
Do no harm. Researchers must not…
• Withhold information
• Provide false information
• Exhibit professional incompetence
What is the difference between consent and assent?
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)
1978; issued by National Commission for Protection of
Human Subjects of Biomedical and Behavioral Research
Belmont Report
The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations.
What is the role of the IRB? What type of studies MUST be reviewed?
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
Define:
Equipoise
genuine confidence that an intervention
may be worthwhile (risk vs. benefit) in order to use it in
humans
What officer enforces the regulations of the IRB?
What officers develops regulations for the IRB?
Office of Human Research Protections (OHRP)
Department of Healthand Human Services (DHHS)
Which level of IRB:
– used for ALL interventional trials with
more than minimal/no risk to patients
All medication‐related studies
Full Board
Which level of IRB:
has minimal risk and no patient identifiers
Expedited
Which level of IRB:
has no patient identifiers, low/no risk, de‐
identified dataset analysis, environmental studies, use
of existing data/specimens (de‐identified)
Exempt
Do studies that qualify for exempt level of IRB have to be submitted at all?
YES
WHO gets to decide level of review?
The IRB
What does the Data Safety & Monitoring Board (DSMB) do?
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
When managing drop outs/ LTFs:
Intent‐to‐Treat (most conservative decision) involves..
• 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)
Intent‐to‐Treat results in what?
Preserves randomization process
Preserves baseline characteristics and group balance at
baseline which controls for known and unknown confounders
Maintains statistical power (original sample size)
If a patient wants to / have to switch groups, this would be defined as:
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
The third option other than as treated and intent-to-treat would be:
to ignore themm (include only compliant or completing
subjects)
What are ways you could assess adherence (compliance)?
o Drug levels (multiple useful sites)
o Pill counts at each visit
o Bottle counter‐tops
What are some ways you could improve adherence (compliance)?
o Frequent follow‐up visits/Communications
o Treatment alarms/notifications
o Medication blister packs or dosage containers
CHEST GUIDELINES? Do we need to know?
