Statistical Principles for Clinical Trials E9 (R1)

Question 1

Estimand

Answer 1

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.

Question 2

Estimate

Answer 2

A numerical value computed by an estimator

Question 3

Estimator

Answer 3

A method of analysis to compute an estimate of the estimand using clinical trial data.

Question 4

Intercurrent Events

Answer 4

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.

Question 5

Missing Data

Answer 5

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

Question 6

Principal Stratification

Answer 6

Classification of subjects according to the potential occurrence of an intercurrent event on all treatments.

Question 7

With two treatments, there are four principal strata with respect to a given intercurrent event:

Answer 7

• 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.

Question 8

Sensitivity Aanlysis

Answer 8

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

Question 9

Supplementary Analysis

Answer 9

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.

Question 10

Statistically speaking, what sequence should trial planning proceed in?

Answer 10

Trial Objective > Estimand > Main Estimator > Main Estimate

Trial Objective > Estimand > Main Estimator > Sensitivity Esimator 1 (2, 3, ..) > Sensitivity Estimate 1 (2, 3, …)

Question 11

The statistical trial planning sequence enables proper trial planning that distinguishes between:

Answer 11

• The target of estimation (trial objective, estimand)
• The method of estimation (estimator)
• The numerical result (estimate)
• Sensitivity analysis

Question 12

Treatment Effects

Answer 12

How the outcome of treatment compares to what would have happened to the same subjects under alternative treatment

Question 13

Central questions for drug development and licensing are to establish the existence, and to estimate the magnitude, of:

Answer 13

Treatment effects

Question 14

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:

Answer 14

Targeted treatment effect

Question 15

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:

Answer 15

Intercurrent events are reflected in the clinical question of interest

Question 16

It is necessary to address intercurrent events when describing the clinical question of
interest in order to precisely define what?

Answer 16

The treatment effect that is to be estimated

Question 17

True/False:
Like missing data, intercurrent events should be thought of as a drawback to be avoided in clinical trials.

Answer 17

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

Question 18

Will discontinuation of treatment affect interpretation of the outcome measurements indefinitely or temporarily?

Answer 18

Indefinitely

Question 19

Will short-term use of additional treatment affect interpretation of the outcome measurements indefinitely or temporarily?

Answer 19

Temporarily

Question 20

In a clinical trial, additional or alternative treatments are often identified as:

Answer 20

• Background treatment
• Rescue medication
• Prohibited medication

This distinguishes their different roles and allows them to be considered separately.

Question 21

What are the strategies for addressing intercurrent events when defining the clinical question of interest?

Answer 21

• Treatment policy strategy
• Hypothetical strategies
• Composite variable strategies
• While on treatment strategies
• Principal stratum strategies

Question 22

The occurrence of the intercurrent event is considered irrelevant in defining the treatment effect of interest:

Answer 22

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.

Question 23

In general, the treatment policy strategy cannot be implemented for intercurrent events that are terminal events, why?

Answer 23

Since values for the variable after the intercurrent event do not exist

Question 24

In hypothetical strategies, a scenario is envisaged in which the intercurrent event would not occur:

Answer 24

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.

Question 25

If a hypothetical strategy is proposed, what should be made clear?

Answer 25

What hypothetical scenario is envisaged

Question 26

True/False: It is necessary to use the strategy to address all intercurrent events when defining the clinical question of interest.

Answer 26

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.

Question 27

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?

Answer 27

The composite variable strategies

Question 28

What is the most salient example of the need for the composite strategy? Why?

Answer 28

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.

Question 29

For the While on treatment strategy, what is of interest?

Answer 29

Response to treatment prior to the occurrence of the intercurrent event

Question 30

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:

Answer 30

Restricting the observation time of interest to the time before the intercurrent event

Question 31

Which strategy relates to the population of interest?

Answer 31

The principal stratum strategy

Question 32

In the principal stratum strategy, the clinical question of interest relates to the treatment effect only within what?

Answer 32

The principal stratum

Question 33

What is it important to distinguish "principal stratification" from?

Answer 33

Subsetting based on actual intercurrent events. (Principal stratification is based on POTENTIAL intercurrent events.)

Question 34

Which attributes are used to construct the estimand, defining the treatment effect of interest?

Answer 34

- Treatment - Population - Variable - Other intercurrent events - Population-level summary

Question 35

What does treatment include when considering it as an estimand attribute?

Answer 35

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.

Question 36

What does population include when considering it as an estimand attribute?

Answer 36

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.

Question 37

What does variable include when considering it as an estimand attribute?

Answer 37

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.

Question 38

What does other intercurrent events include when considering it as an estimand attribute?

Answer 38

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

Question 39

What does population-level summary include when considering it as an estimand attribute?

Answer 39

A population-level summary for the variable should be specified, providing a basis for comparison between treatment conditions.

Question 39

The construction of an estimand should consider what is of clinical relevance for the particular treatment in the particular therapeutic setting. Considerations include:

Answer 39

- 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.

Question 40

Clear specifications for the treatments of interest might already reflect multiple relevant intercurrent events. Specifically, a treatment might already reflect the:

Answer 40

- Clinical question of interest in respect of changes in background treatment - Concomitant medications - Use of additional or later-line therapies - Treatment-switching - Conditioning regimens

Question 41

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?

Answer 41

No

Question 42

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?

Answer 42

Yes

Question 43

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?

Answer 43

An alternative estimand, trial design and method of analysis

Question 44

Avoiding or over-simplifying the process of discussing and constructing an estimand risks:

Answer 44

Misalignment between trial objectives, trial design, data collection and method of analysis

Question 45

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?

Answer 45

The choice of data collection and method of analysis

Question 46

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:

Answer 46

Trials where a non-inferiority or equivalence hypothesis is used in order to establish and quantify evidence of efficacy.

Question 47

What does the design of a trial need to be aligned to?

Answer 47

The estimands that reflect the trial objectives

Question 48

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:

Answer 48

- 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

Question 49

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?

Answer 49

Multiplicity

Question 50

An estimand for the effect of treatment relative to a control will be estimated by comparing:

Answer 50

The outcomes in a group of subjects on the treatment to those in a similar group of subjects on the control.

Question 51

For a given estimand, what should be implemented that is able to provide an estimate on which reliable interpretation can be based?

Answer 51

An aligned method of analysis, or estimator

Question 52

The robustness of the results to potential departures from the underlying assumptions should be assessed through:

Answer 52

An estimand-aligned sensitivity analysis

Question 53

Does estimation that relies on many or strong assumptions require more or less extensive sensitivity analysis?

Answer 53

More

Question 54

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?

Answer 54

A sensitivity analysis

Question 55

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?

Answer 55

The sponsor and regulator

Question 56

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:

Answer 56

Supplementary analysis

Question 57

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:

Answer 57

Sensitivity analysis.

Question 58

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?

Answer 58

Supplementary analyses for an estimand. They generally play a lesser role interpretation of trial results.

Question 59

Analyses should be planned using what two data sets so that differences between them can be the subject of explicit discussion and interpretation?

Answer 59

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.

Question 60

Why might results from an analysis using the PPS be subject to severe bias?

Answer 60

Analysis of the PPS does not achieve the goal of estimating the effect in any principal stratum.

Question 61

A trial protocol should define and specify explicitly a primary estimand that corresponds to the:

Answer 61

Primary trial objective

Question 62

What is usually the main determinant for aspects of trial design, conduct and analysis?

Answer 62

The choice of the primary estimand

Question 63

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.

Answer 63

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.