Statistical Principles for Clinical Trials E9 (R1) Flashcards
Estimand
A precise description of the treatment effect reflecting the clinical question posed by the trial objective. It summarizes at a population-level what the outcomes would be in the same patients under different treatment conditions being compared.
Estimate
A numerical value computed by an estimator
Estimator
A method of analysis to compute an estimate of the estimand using clinical trial data.
Intercurrent Events
Events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question of interest. It is necessary to address intercurrent events when describing the clinical question of interest in order to precisely define the treatment effect that is to be estimated.
Missing Data
Data that would be meaningful for the analysis of a given estimand but were not collected. They should be distinguished from data that do not exist or data that are not considered meaningful because of an intercurrent event
Principal Stratification
Classification of subjects according to the potential occurrence of an intercurrent event on all treatments.
With two treatments, there are four principal strata with respect to a given intercurrent event:
- Subjects who would not experience the event on either treatment
- Subjects who would experience the event on treatment A but not B
- Subjects who would experience the event on treatment B but not A
- Subjects who would experience the event on both treatments.
Sensitivity Aanlysis
A series of analyses conducted with the intent to explore the robustness of inferences from the main estimator to deviations from its underlying modelling assumptions and limitations in the data
Supplementary Analysis
A general description for analyses that are conducted in addition to the main and sensitivity analysis with the intent to provide additional insights into the understanding of the treatment effect.
Statistically speaking, what sequence should trial planning proceed in?
Trial Objective > Estimand > Main Estimator > Main Estimate
Trial Objective > Estimand > Main Estimator > Sensitivity Esimator 1 (2, 3, ..) > Sensitivity Estimate 1 (2, 3, …)
The statistical trial planning sequence enables proper trial planning that distinguishes between:
- The target of estimation (trial objective, estimand)
- The method of estimation (estimator)
- The numerical result (estimate)
- Sensitivity analysis
Treatment Effects
How the outcome of treatment compares to what would have happened to the same subjects under alternative treatment
Central questions for drug development and licensing are to establish the existence, and to estimate the magnitude, of:
Treatment effects
The targets of estimation are to be defined in advance of a clinical trial. Once defined, a trial can be designed to enable reliable estimation of the:
Targeted treatment effect
The description of an estimand involves precise specifications of certain attributes, which should be developed based not only on clinical considerations but also on how:
Intercurrent events are reflected in the clinical question of interest
It is necessary to address intercurrent events when describing the clinical question of
interest in order to precisely define what?
The treatment effect that is to be estimated
True/False:
Like missing data, intercurrent events should be thought of as a drawback to be avoided in clinical trials.
False.
UNLIKE missing data, intercurrent events are NOT to be thought of as a drawback to be avoided in clinical trials.
Discontinuation of prescribed treatment, use of additional medication, and other such events may occur in clinical practice as they do in clinical trials, and their occurrence needs to be considered explicitly when defining the clinical question of interest
Will discontinuation of treatment affect interpretation of the outcome measurements indefinitely or temporarily?
Indefinitely
Will short-term use of additional treatment affect interpretation of the outcome measurements indefinitely or temporarily?
Temporarily
In a clinical trial, additional or alternative treatments are often identified as:
- Background treatment
- Rescue medication
- Prohibited medication
This distinguishes their different roles and allows them to be considered separately.
What are the strategies for addressing intercurrent events when defining the clinical question of interest?
- Treatment policy strategy
- Hypothetical strategies
- Composite variable strategies
- While on treatment strategies
- Principal stratum strategies
The occurrence of the intercurrent event is considered irrelevant in defining the treatment effect of interest:
The value for the variable of interest is used regardless of whether or not the
intercurrent event occurs.
For example, when specifying how to address use of additional medication as an intercurrent event, the values of the variable of interest are used whether or not the patient takes additional medication.
In general, the treatment policy strategy cannot be implemented for intercurrent events that are terminal events, why?
Since values for the variable after the intercurrent event do not exist
In hypothetical strategies, a scenario is envisaged in which the intercurrent event would not occur:
The value of the variable to reflect the clinic question of interest is the value which the variable would have taken in the hypothetical scenario defined.
If a hypothetical strategy is proposed, what should be made clear?
What hypothetical scenario is envisaged
True/False:
It is necessary to use the strategy to address all intercurrent events when defining the clinical question of interest.
False.
It is NOT necessary to use the strategy to address all intercurrent events when defining the clinical question of interest.
Indeed, different strategies will often be used to reflect the clinical question of interest in respect of different intercurrent events.
What strategy can be viewed as implementing the intention-to-treat principle in some cases where the original measurement of the variable might not exist of might not be meaningful, but where the intercurrent event itself meaningfully describes the patient’s outcome?
The composite variable strategies
What is the most salient example of the need for the composite strategy? Why?
Terminal events.
If a treatment saves lives, its effect on various measures in surviving
patients may be of interest, but it would be inappropriate to say that the summary measure of interest was only the average value of some numerical measure in survivors.
For the While on treatment strategy, what is of interest?
Response to treatment prior to the occurrence of the intercurrent event
Like the composite variable strategy, the while on treatment strategy can hence be thought of as impacting the definition of the variable, in this case by:
Restricting the observation time of interest to the time before the intercurrent event
Which strategy relates to the population of interest?
The principal stratum strategy
In the principal stratum strategy, the clinical question of interest relates to the treatment effect only within what?
The principal stratum
What is it important to distinguish “principal stratification” from?
Subsetting based on actual intercurrent events. (Principal stratification is based on POTENTIAL intercurrent events.)
Which attributes are used to construct the estimand, defining the treatment effect of interest?
- Treatment
- Population
- Variable
- Other intercurrent events
- Population-level summary
What does treatment include when considering it as an estimand attribute?
The treatment condition of interest and, as appropriate, the alternative treatment condition to which comparison will be made.
These might be individual interventions, combinations of interventions administered concurrently, or might consist of an overall regimen involving a complex sequence of interventions.
What does population include when considering it as an estimand attribute?
The population of patients targeted by the clinical question.
This will be represented by the entire trial population, a subgroup defined by a particular characteristic measured at baseline, or a principal stratum defined by the occurrence (or non-occurrence, depending on context) of a specific intercurrent event.
What does variable include when considering it as an estimand attribute?
The variable (or endpoint) to be obtained for each patient that is required to address the clinical question.
The specification of the variable might include whether the patient experiences an intercurrent event.
What does other intercurrent events include when considering it as an estimand attribute?
Precise specifications of treatment, population and variable are likely to address many of the intercurrent events considered in sponsor and regulator discussions of the clinical question of interest. The clinical question of interest in respect of any other intercurrent events will usually be reflected using the strategies introduced as treatment policy, hypothetical or while on treatment
What does population-level summary include when considering it as an estimand attribute?
A population-level summary for the variable should be specified, providing a basis
for comparison between treatment conditions.
The construction of an estimand should consider what is of clinical relevance for the particular treatment in the particular therapeutic setting. Considerations include:
- The disease under study
- The clinical context (e.g. the availability of alternative treatments)
- The administration of treatment (e.g. one-off dosing, short-term treatment or chronic dosing)
- The goal of treatment (e.g. prevention, disease modification, symptom control)
Also important is whether an estimate of the treatment effect can be derived that is reliable for decision making.
Clear specifications for the treatments of interest might already reflect multiple relevant intercurrent events. Specifically, a treatment might already reflect the:
- Clinical question of interest in respect of changes in background treatment
- Concomitant medications
- Use of additional or later-line therapies
- Treatment-switching
- Conditioning regimens
If a treatment is specified as intervention A added to background therapy B, dosed as required, would changes to the dose of background therapy B need to be considered as an intercurrent event?
No
If a treatment is specified as intervention A added to background therapy B, dosed as required, does the use of an additional therapy need to be considered an intercurrent event?
Yes
Where significant issues exist to develop an appropriate trial design or to derive an adequately reliable estimate for a particular estimand, what needs to be considered?
An alternative estimand, trial design and method of analysis
Avoiding or over-simplifying the process of discussing and constructing an estimand risks:
Misalignment between trial objectives, trial design, data collection and method of analysis
Whilst an inability to derive a reliable estimate might preclude certain choices of strategy, it is important to proceed sequentially from the trial objective and an understanding of the clinical question of interest, and not for what to determine the estimand?
The choice of data collection and method of analysis
When selecting strategies, it might be important to distinguish between trials
designed to detect whether differences exist between treatments containing the same or similar active substance (e.g. comparison of a biosimilar to a reference treatment) and:
Trials where a non-inferiority or equivalence hypothesis is used in order to establish and quantify evidence of efficacy.
What does the design of a trial need to be aligned to?
The estimands that reflect the trial objectives
Clear definitions for the estimands on which quantification of treatments effects will be based should inform the choices that are made in relation to trial design. This includes:
- Determining the inclusion and exclusion criteria that identify the target population
- The treatments including the medications that are allowed and those that are prohibited in the protocol
- Other aspects of patient management and data collection
What issues could arise, and need to be addressed, from having a trial with multiple objectives, and therefore multiple estimands, each associated with statistical testing and estimation?
Multiplicity
An estimand for the effect of treatment relative to a control will be estimated by comparing:
The outcomes in a group of subjects on the treatment to those in a similar group of subjects on the
control.
For a given estimand, what should be implemented that is able to provide an estimate on which reliable interpretation can be based?
An aligned method of analysis, or estimator
The robustness of the results to potential departures from the underlying assumptions should be assessed through:
An estimand-aligned sensitivity analysis
Does estimation that relies on many or strong assumptions require more or less extensive sensitivity analysis?
More
Inferences based on a particular estimand should be robust to limitations in the data and deviations from the assumptions used in the statistical model for the main estimator. What should this robustness be evaluated through?
A sensitivity analysis
Sensitivity analysis should be planned for the main estimators of all estimands that will be important for regulatory decision making and labelling in the product information. This can be a topic for discussion and agreement between who?
The sponsor and regulator
Distinct from sensitivity analysis, where investigations are conducted with the intent of exploring robustness of departures from assumptions, other analyses that are conducted in order to more fully investigate and understand the trial data can be termed:
Supplementary analysis
Interpretation of trial results should focus on the main estimator for each agreed estimand providing that the corresponding estimate is verified to be robust through the:
Sensitivity analysis.
What kind of analyses can be conducted in addition to the main and sensitivity analysis to provide additional insights into the understanding of the treatment effect?
Supplementary analyses for an estimand.
They generally play a lesser role interpretation of trial results.
Analyses should be planned using what two data sets so that differences between them can be the subject of explicit discussion and interpretation?
The full analysis set (FAS) and the per protocol set (PPS).
Consistent results from analyses based on the FAS and the PPS is indicated as increasing confidence in the trial results.
Why might results from an analysis using the PPS be subject to severe bias?
Analysis of the PPS does not achieve the goal of estimating the effect in any principal stratum.
A trial protocol should define and specify explicitly a primary estimand that corresponds to the:
Primary trial objective
What is usually the main determinant for aspects of trial design, conduct and analysis?
The choice of the primary estimand
True/False:
It is to the benefit of the sponsor to have clarity on what is being estimated, therefore it is a regulatory requirement to document an estimand for each exploratory objective.
False.
While it is to the benefit of the sponsor to have clarity on what is being estimated, it is NOT a regulatory requirement to document an estimand for each exploratory objective.
