Lecture 16-19 Interventional Study Designs Flashcards
Key Differences Between Interventional and Observational Study Designs
Interventional: clinical trial/study, experimental study, human study, investigational study
- investigator selects “interventions” and allocates study subjects to forced intervention groups
- more “rigorous” in ability to show cause-and-effect
- can demonstrate causation
Phases of Interventional Studies
Pre-clinical= prior to human investigation (bench and animal research)
- trends moving from phase 1-4:
1. population size increases
2. longer duration
3. change in focus (safety-efficacy-back to safety)
4. phase 1 is only one with healthy subjects and phase 4 must be post approval (post marketing)
Phase 1
- new drug/device/procedure
- small sample size (20-80)
- healthy volunteers or used for the first time in humans to asses safety/toxicity/dosing/pharmokinetics in the diseased population
- short duration (few days-month)
- SAFETY primary purpose
Phase 2
- new drug/device/procedure, indication/study population
- larger sample size (100-300)
- use patients with condition of interest, expand on purpose of phase 1 (safety) but ALSO being assessing efficacy is diseased population
- short-medium duration (few months)
- have narrower inclusion criteria (tend to be restrictive to people w/disease of interest, no comorbidities and no other drugs)
Phase 3
- new drug/device/procedure, indication or study population
- even large sample size (1,000-3,000)
- used in patients w/condition of interest to continue determination of safety BUT primary purpose to assess efficacy
- longer duration (months-year)
- assess superiority, non-inferiority, equivalency
Phase 4
- post marketing/always after the drug/device/procedure approval
- long term effects in a large population of diseased patients (expanded use population)
- registries/surveys (collect info from patients on drugs, looking for temporality, documentation, etc.)
examples: Medwatch, FAERS, VAERS
Advantages of Interventional Trials
-cause precedes effect (shows causation)
- only design used by FDA for “approval” process on label
- vital steps in approval process, phase 1-3 need to show benefits in use to make a phase 4 study
Disadvantages of Interventional Trials
- expensive
- complex/takes time (development/approval/conductance)
- ethical considerations (never force people to smoke/drink) *usually the #1 reason observational studies are used instead
- generalizability (external validity)= greatest flaw, restrictive to co-morbidities/drugs use to isolate the effects of disease of interest (prove causation) but since restrictive it does not apply to general public (patients going to clinics with other co-morbidities/medications)
Explanatory Interventional Study
- Not the usual way to make clinical designs (rule book/restrictions must be followed)
- use placebos
example: patients get put on same dose medication but some people need more or less and with rule book you cannot change dose or adjust measures like in a real clinical setting (no flexibility) - less external validity , too restrictive
Pragmatic Interventional Studies
- use normal clinical setting where there are patients with multiple co-morbidities and doctors can prescribe individual dosing to patients (let in “regular” patients)
- never use placebo (compare real drug to real drug)
- researchers loose control over how physician prescribes medications and group allocation/restriction
- additional confounding with co-morbidities
- more flexible and more external validity
- less able to prove causation
Simple Study Design
- divides (randomizes) subjects exclusively into 2+ groups
- SINGLE randomization
- used to test SINGLE hypothesis
Factorial Study Design
- divides subjects into 2+ groups and then further subdivides each groups into 2+ subgroups
- used to test MULTIPLE hypotheses at the same time (useful for combination therapy)
- must increase sample size
- improves efficacy for answering clinical questions
- increases complexity (could be barrier to recruitment)
- increases risk of drop outs (due to increase complexity)
- may restrict generalizability of results
Parallel Study Design
- groups simultaneously and exclusively managed
- no switching of intervention groups after initial randomization
- *All simple and factorial study designs
- worry if people are equal in every aspect (want to limit differences between groups)
Cross-Over Study Design
- self control
- groups serve as their own control by crossing over from one intervention to the other during the study
- allows for small sample size (each patient contributes additional data)
- don’t way about differences between groups because the same people contribute to both groups
- between groups comparison= all group a vs all group b
- within groups comparison= person while in group a vs same person while in group b
Wash Out
- longest period you need for each group to get it all cleaned out (back to baseline)
- all effects eliminated
- want to avoid hangover (don’t want lingering effects from other therapy, want all effects gone before person starts other therapy)
Lead in phase
- practice period
- can also function like a wash out period
- let patients practice to see if they can accomplish everything required
- placebo will be taken
- at the end of lead in phase bring subjects back if they can complete and comply with the process at a certain level (usually 80-90%)
- drop them out of the study if don’t meet standards
Disadvantages of Cross Over Design
- only suitable for long term conditions which are not curable or which treatment provides short term relief
- duration of study for each subject is longer
- carry over effects (try to wash out)
- treatment by period interaction (differences in effects of treatments during different time periods)
- complexity in data analysis
Outcomes/Endpoints:
Primary
- most important key outcome(s)
- main research question used for developing/conducting study
- main purpose of the study
Outcomes/Endpoints
Secondary
- lesser importance yet still valuable
- possible for future hypothesis generation
- secondarily while I am at it I will ask about…..
- not primary purpose of the study
Outcomes/Endpoints
Composite
- combines multiple endpoints into a single outcome
- could be considered the primary outcomes and if so then secondary outcomes may be the individual elements from the composite outcome
example: main purpose of the study is to assess outcome of MI, stroke, or death (composite) - each one individually is secondary outcome
Outcomes/Endpoints
Patient Oriented Endpoints
- most clinically relevant
ex: death, stroke, MI, hospitalization, preventing dialysis - direct: mean things to patients, prevent cancer/death, prolong survival
- more useful and impactful
Outcomes/Endpoints
Surrogate Markers
- elements used in place of evaluating patient oriented (direct) endpoints
- not the only reason someone might have disease
ex: blood pressure, cholesterol, change in SCr levels - study can start off looking at surrogates and move into more clinically relevant direct outcomes
Non-Random Group Allocation
- subjects do NOT have an equal probability of being selected or assigned to each intervention group
- convenience sampling or non-probabilistic allocation
- can sound purposeful and pre-subscribed but it is NOT random
ex: patients attending morning clinic assigned to group 1 and patients attending afternoon clinic assigned group 2
ex: first 100 people admitted to the hospital
Random Group Allocation (most utilized)
- subjects do have an equal probability of being assigned to each intervention group
- goal is to make groups as equal as possible and takes allocation process away from research
- uses random number generating program