[2] Class 16-19:Interventional studies Flashcards
What form of study allows for causation?
Interventional study
Type of study in which Researchers intervene and force ppl into groups allocating Tx
Interventional study
Which process commonly utilized to accomplish forced allocation in interventional studies?
Randomization
Which study is considered natural?
Observational
Type of study where researchers observe subject elements occurring that’re selected by the individual
Observational
What study type is not able to prove causation:
Observational
Form of researcher forced allocation in observational studies
There is no researcher forced group allocation
Human study,clinical trial/study,experimental, investigational study generally means
interventional study
Name the key difference in Interventional vs. observational studies:
Investigator selects “interventions” and allocates study subjects to intervention groups
It is more rigorous in ability to show cause-and-effect: IT CAN PROVE
Phases of interventional studies:
Pre-clinical-Phase 0-phase 4
Phase of the study at the lab ‘bench’ or animal investigation
Pre-clinical
Exploratory investigational new drug
Phase 0
3 factors to consider when looking at phases of interventional studies:
Sample size,
Length of study,
Purpose-of phase
Very small
Phase 0
Pharmacokinetics:
ADME
Absorption
Distribution
Metabolism
Excretion
Primary purpose is kinetics of the drug:
Phase 0
small 20-80 N- short duration-few weeks,
Healthy or diseased volunteers
Possible first time use in ppl,
Phase 1
Primary purpose: side effects
Secondary: does it actually do what it was set out to do [lower BP/BG]
Phase 1
Investigational New drug
Phase 1
Does safety remain a purpose after it is the primary purpose in phase 1?
Yes, it just is not be the primary purpose
Investigational new drug;indication/population
Phase 2
Medium N-100-300 and medium duration-few weeks to few months;
Commonly utilize patients w/ Dz of interest…begins to assess efficacy in diseased
Phase 2
Randomization think->
Interventional
First phase that begins to look at efficacy:
Phase 2
Which phase is likely to have narrow inclusion criteria?
Phase 2
Large N 500-3,000 Longer duration:months-yrs Ppl have dz of interest Assessing for short-intermediate safety Broader inclusion criteria-more clinically relevant
Phase 3
Primary purpose is to assess for efficacy:
Phase 3
The concern w/ more restrictions on exclusions:
More restrictions = more specific and less generalizability
Post-marketing post-FDA approval phase:
Phase 4
What phase is req’d for FDA approval:
Phase 3
Larger N -1000s
Long term effects
Dz population
CAN be interventional or observational design
Phase 4
Is phase 0-4 sequential and req’d?
No can go in any order but phase 3 must be approved by FDA
FDAs medwatch is an example of what phase :
Phase 4
Which study is perfect?
NONE
Advantages of interventional trials:
Can prove causation
Only design that can be used for FDA approval
Disadvantages of Interventional trial:
Cost
Complexity/time
Ethical considerations
Generalizability-External valid.
What is the number one disadvantage to interventional trials?
Ethical considerations are the # 1 reasons why they’re not completed
Loosens inclusion criteria/ controlling of intervention
More real life/more variable
Allows for others to be doctor of study
Pragmatic interventional study
An interventional study w/ a single randomization process and no more subsequently
Simple interventional study
Interventional study with 2 or more groups that are randomized into 2 or more sub-groups
Factorial interventional study
Ex of factorial study
Fish oil vs. placebo->
Fish oil and niacin vs. placebo and niacin.
Types of factorial:
2x2; 2x2x2
Can factorial designs be used to test multiple hypotheses/questions at the same time
Yes
BEnefits of factorial design
- Improved efficiency for answering clinical questions
- req larger study population
Disadvantages to factorial interventional study
Increased complexity-barrier for recruitment
Increased risk of drop out[d/t complexity]
May restrict generalizability of results
Interventional study where groups simultaneously and exclusively managed
No switching of intervention groups after initial randomization
Parallel interventional study
All simple and factorial designs can be
Parallel
Interventional study that groups serve as their own control by crossing over from one intervention to another during the study
Cross-over
This study type allows for a smaller total n population -sample size
Cross-over study
Study that self-controls for cofounders b/c same individual is receiving both Tx / interventions
Cross-over
This time period is when the person is cleansing drug/Tx from body prior to receiving other drug/Tx
Wash-out period
Cross-over study is typically for what type of disease/condition?
Chronic disease- long standing b/c it it wouldn’t be helpful to cure then taker another Tx regime.
This can be used to assess placebo-effects, hawthorne-effects and compliance before the study begins:
Run-in; lead-in phase
All study subjects blindly given placebo(s) for initial therapy [defined time period] to determine a “new” base-line of disease [satndardization]
Test run= complaisance assessment
Washout period p/t study or can wash-out existing Rx
Run-in / lead-in phase
Disadvantages for cross-over study designs:
- Only suitable for long-term conditions- not curable [short term relief]
- duration of study for each subject is longer
- carryover effect during washout
- Tx by time period interaction
- complexity in data analysis
- smaller N req’ment applies only sometimes
Most important key outcome
It is the main research question/hypothesis for conducting study
Primary outcomes
Lesser importance yet still valuable outcome
Possible for future hypothesis generation
Secondary/tertiary/etc. outcome
Combines multiple endpoints into a single outcome
Can be considered primary outcome and secondary outcomes can be individual outcome elements
Composite outcome
Ex of POEMs (patient oriented endpoints
Death, stroke, MI, hospitalization, preventing need for dialysis
Ex of DOEs Disease oriented endpoints
Risk for stroke
Risk for MI
Worsening in renal function
Sample selection in which subjects don’t have equal probability of being selected or assigned to each intervention group
“First couple of people that happen to walk by”
Non-random sample selection
Sample selection in which Subjects do have an equal probability of being assigned to each intervention group
Created by random number generators
Random sample selection(most commonly utilized
Random sampling hopefully removes:
Bias
What is the purpose to randomization:
To make groups as equal as possible
Attempts to reduce systematic diffferences [bias] between groups that could impact results
Based on known and unknown factors [confounders]
Randomization
W/ randomization is equality guaranteed?
NO not guaranteed
Which table typically shows group characteristics such as possible cofounders and p values:
Table 1
Table 1
Documentation of equality of groups [effectiveness of randomization process] reported in 1 of several locales : p values
3 types of randomization
Simple
Blocked
Stratified
Equal probability for allocation within one of the study groups
Basic randomization- hopeful
Simple randomization
Ensures balance within each intervention groups
When researchers want to assure that all groups are equal in size
More hands on approach for researcher-when study req’s exact #’s
Blocked randomization
Ensures balance w/ known confounding variables
Ex: age, Dz, gender, comorbidities
Can also pre-select levels to be balanced w/in each interfering factor [cofounder]
More hands on approach for researchers
Stratified randomization
3 types of masking:
Single-blind
Double-blind
Open-label
Masking in which study subjects aren’t informed which intervention theyre receiving [but clinician/researchers know]
Single-blind masking
Masking in which neither investigators nor study subjects are informed which intervention each subject is receiving
Double-blind masking
Masking in which everyone knows which intervention each subject is receiving
Open-label
How would you test a IM shot vs. PO tablet
Make each group receives both types of intervention, no matter which route is true Rx to prevent bias
What can be used to asses adequacy of blinding?
Post hoc surveys
Inert Tx made to look identical in all aspects to active Tx
Placebo / dummy therapy
What is it called if more than 1 placebo / dummy therapy is used
Double-dummy
Improvement in conditions by power of suggestion and due to the care provided
Can be as large as 30-50%
Placebo effect
Desire of the study subject to “please” investigators by reporting positive results [improvement], regardless of Tx allocation
Desire for positive outcomes
Hawthorne effect
Hawthorne effect can make up part of the rate of:
Placebo effect
Define post hoc subgroups analysis
A stepwise multiple comparisons procedure used to identify sample means statistically different from each other
When is post-hoc sub-group analysis accepted?
It is accepted as appropriate by most when it is prospectively planned for hypothesis generation
When is post-hoc sub-group analysis not accepted?
Not accepted as appropriate when its not prospectively planed
When post-hoc sub-group analysis is not accepted, what is the term used to define how the stat was found?
‘Fishing’ or ‘data-dredging’
Why is fishing or data dredging not a good thing? 2 reasons
Reduces Power
And
Increases risk of type 2 error
What should be included in the sample size determination?
Add in for anticipated drop-outs/ lost to F/u
3 ways to manage drop-out/lost to f/u rates:
Intention to treat
Per-protocol or efficacy-analysis
As treated
Which way of managing drop-outs is most conservative?
Intent(ion)-to-treat
2 procedures for intent to treat:
Last known asssessment used for all subsequent, yet MISSED assessments
Convert subsequent missed assessments for a subject to null-effect (no benefit/change)
Do authors tell you how they manage drop-out?
Yes, authors must disclose the form of drop-out management they will use
Results of intent to treat [3]:
- Preserves randomly selected process
- preserves baseline characteristics and group balance at baseline which controls for known and unknown confounders
- maintains statistical power
Technique of ignoring drop-outs
Including only compliant subjects
Per-protocol or efficacy analysis
What is the customarily set rate of compliance w/ per protocol or efficacy analysis?
80-90%
Technique where drop-outs of study are treated
‘As-treated’
Technique for managing drop-outs that allows ignoring group assignments-allows subjects to switch groups and be evaluated in group they moved to, end in, or stay in most
‘As-treated’
Per-protocol dropout management technique results in:
Biases estimates of effect (commonly over-estimates effects)
Reduces generalizability
Ways to assess compliance/adherence
Drug levels
Pill counts
Pill bottle counters [lids]
Why is adherence used more than compliance now?
Compliance has a negative connotation to it by being forceful.
Adherence allows pt in decision making process…kind of
Methods to improve adherence:
Frequent f/u visits [communication]
Tx alarms/ notifications
Rx blister packs or dosage containers
