Statistical Principles for Clinical Trials E9 Flashcards
What is the broad aim of the process of clinical development of a new drug?
To find out whether there is a dose range and schedule at which the drug can be shown to be simultaneously safe and effective, to the extent that the risk-benefit relationship is acceptable.
Clinical plan(s) should be flexible enough to:
Allow for modification as knowledge accumulates.
Interpretation and assessment of the evidence from the total program of trials involves synthesis of the evidence from the individual trials. This is facilitated by ensure that common standards are adopted for a number of features of the trials such as:
- Dictionaries of medical terms
- Definition and timing of the main measurements
- Handling of protocol deviations
When would a statistical summary, overview, or meta-analysis be informative?
When medical questions are addressed in more than one trial.
As a rule, confirmatory trials are necessary to provide:
Firm evidence of efficacy or safety
In a confirmatory trial it is equally important to:
- Estimate with due precision the size of the effects attributable to the treatment of interest
- Relate these effects to their clinical significance
Firm evidence in support of claims requires that the results of the confirmatory trials demonstrate that the investigational product under test has:
Clinical benefits
In a confirmatory trial, it is important that the basis for generalization to the intended patient population is understood and explained. What does this influence?
The number and type of centers and/or trials needed.
Regarding objectives, how do exploratory trials differ from confirmatory trials?
The objectives of exploratory trials may not always lead to simple tests of pre-defined hypotheses.
True/False:
Confirmatory trials may sometimes require a more flexible approach to design so that changes can be made in response to accumulating results.
False.
EXPLORATORY trials may sometimes require a more flexible approach to design so that changes can be made in response to accumulating results.
The analysis of exploratory trials may entail data exploration; tests of hypothesis may be carried out, but the choice of hypotheses may be data dependent. This is why such trials cannot be the basis of the:
Formal proof of efficacy.
They may still contribute to the total body of relevant evidence though.
True/False:
Any individual trial may have both confirmatory and exploratory aspects.
True
By which trial phase should the inclusion and exclusion criteria relax, so that the subjects in the trials more closely mirror the target population?
Confirmatory trial
Primary Variable (Target Variable, Primary Endpoint)
The variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial.
In general, how many primary variables should there be?
One
What kind of variable will the primary variable usually be?
Efficacy variable
There should be sufficient evidence that the primary variable can provide:
A valid and reliable measure of some clinically relevant and important treatment benefit in the patient population described by the inclusion and exclusion criteria.
Generally, which variable should be the one that determines sample size?
Primary variable
Why is it important that subject outcome be carefully defined?
In many cases, the approach to assessing subject outcome may not be straightforward.
There are many possible approaches to assessing subject outcome, such as:
- Comparisons of the assessments done at the beginning and end of the interval of observation
- Comparisons of slopes calculated from all assessments throughout the interval
- Comparisons of the proportions of subjects exceeding or declining beyond a specified threshold
- Comparisons based on methods for repeated measures data
The primary variable should be specified in the protocol, along with:
The rationale for its selection
True/False:
Redefinition of the primary variable after unblinding will almost always be acceptable.
False.
Redefinition of the primary variable after unblinding will almost always be UNACCEPTABLE, since the biases this introduces are difficult to assess.
When the clinical effect defined by the primary objective is to be measured in more than one way, the protocol should identify one of the measurements as the primary variable on the basis of:
- Clinical relevance
- Importance
- Objectivity
- Other relevant characteristics
Secondary variables are either supportive measurements related to the primary objective or:
Measurements of effects related to the secondary objectives