Midterm - Clinical Trials Flashcards
What are the Prentice Criteria for establishing valid surrogates?
- Treatment affects surrogate
- Surrogate predicts clinical event/ endpoint
- Surrogate fully captures treatment’s effect on the clinical event/ endpoint
What are 2 ways AEs are evaluated?
- Severity
- Relatedness to study drug/ intervention
What are 3 of 5 criteria for AE to be classified as serious adverse event (SAE)?
Event leads to
* death
* hospitalization/ prolonging of existing hospitalization
* disability/ incapacity that’s persistent/ significant
* congenital abnormalities/ birth defects
Or event is life-threatening
What is a SUSAR and how is a SUSAR related to other AEs?
- Suspected: The event is possibly connected to the study drug/ intervention.
- Unexpected: Event is not included on investigator brochure/ approved drug label.
- Severe: SUSARs are a SAE subtype.
- Adverse
- Reaction
What are the benefits & challenges associated with composite endpoints?
BENEFITS
* Potentially more holistic metric
* Larger sample size (i.e. more events)
CHALLENGES
* Components of composite usually vary in severity
and in impact on quality of life. This muddies interpretation.
* Time to event analyses usually focus on 1st event
and ignore multiple events of the same or different
types.
What are two approaches to co-primary endpoint analysis and the tradeoffs of each approach?
Two approaches:
1) Require both endpoints achieve a specific level of
significance for the new treatment to be considered a success (i.e. p < 0.05 for all endpoints)
* Does not inflate type-I error rate
* reduces power
2) Require either endpoint to reach a specific
significance level for the treatment to be considered a success (i.e. p < 0.05 for one co-primary endpoint)
* Inflates type-I error rate (multiple comparison correction needed to control type-I error rate)
* maintains power
What are the advantages and disadvantages of simple and permuted block randomization?
SR:
* Pro: Easy to do, straightforward inference and theoretical analysis.
* Con: Can have chance imbalance in allocation ratio.
PBR:
* Pro: Ensures balanced allocation ratio, and balances against bias from changing participant characteristics.
* Con: Slightly more difficult to implement/ analyze. Also, if the block size is discovered by participant/ provider, unblinding is possible.
What’s a pro and a con of using broad inclusion criteria in clinical trials?
Pro: Recruitment easier. Potentially increased generalizability.
Con: Treatment effect might be specific to subgroup(s), so broad inclusion criteria might dilute such an effect.
Define and give an example of single blind design.
D: Patient is blinded to treatment whereas provider is unblinded.
e.g. surgeon is aware of medical device settings, but patient is not.
Define and give an example of confounding variable.
D: Variable that impacts independent variable (treatment) and dependent variable (endpoint), potentially causing spurious associations.
e.g. coffee drinkers might smoke more cigarettes than non-coffee drinkers. Smoking might act as a confounder in a study of the association between coffee drinking and heart disease.
Does simple randomization (SR)/ permuted block randomization (PBR) have an advantage in the following contexts:
* Allocation concealment in a non-blind study
* Loss of power due to treatment total imbalance
* Changing patient characteristics over time.
SR wins for allocation concealment in a non-blind study since, in PBR, if the size is discovered, providers can anticipate which treatment is to be given next and preferentially enroll certain patients.
PBR wins for
* Loss of power due to treatment total imbalance
* Changing patient characteristics over time.
What randomization method is used to create a pre-stratification randomization schedule? What’s the goal of this randomization method?
Stratified randomization:
1. Stratify
2. Randomize to treatment.
Goal: Balance with respect to prognostic factors.
(This is distinct from permuted block randomization where the goal is to achieve balance with respect to treatment arm over time)
Give 2 advantages of pre-stratification.
- Prevents “accidental bias” resulting from maldistribution of important prognostic variables
- Increases precision (if stratifying variables are
related to outcome) - Ensures balance on stratifying factors in early
interim analyses (even in large trials) - Facilitates subgroup analysis by stratifyng factor (more optimal allocation ratio)
What is the primary disadvantage of pre-stratification?
Logistics involved in implementing several randomization schedules.
Describe intention-to-treat (ITT) and per protocol (PP) analysis in 1-2 sentences.
Intention-to-treat (ITT) analysis includes all randomized participants in the groups to which they were originally assigned, regardless of whether they completed the intervention according to the study protocol.
Per protocol (PP) analysis, on the other hand, includes only those participants who completed the intervention exactly as planned.
