FDA Clinical Trial Estimands and Sensitivity Analysis

Question 1

ICH Achievement, General

(5)

Answer 1

1. Reduced duplicative clinical studies
2. Prevented unnecessary animal studies
3. Standardized safety reporting
4. Standardized marketing application submission
5. Contributed in improvement in drug development, manufacturing and accessibility

Question 2

Intercurrent Event, Examples

(3)

Answer 2

1. discontinuation of assigned treatment
2. use of an additional or alternative treatment
3. terminal events such as death

Neither study withdrawal nor other reasons for missing data are in themselves intercurrent events. Subjects who withdraw from the trial may have experienced an intercurrent event before withdrawal.

Question 3

Intention-To-Treat

(1) that the trial analysis should include ____ subjects relevant for the research question;
(2) that subjects should be included in the analysis as ____; and
(3) as taken directly from the definition of the ITT principle (see ICH E9 Glossary), that subjects should be followed up and assessed ____ of adherence to the planned course of treatment and that those assessments should be used in the analysis.

3 consequences arising from the ITT principle can be distinguished

Answer 3

(1) that the trial analysis should include all subjects relevant for the research question;
(2) that subjects should be included in the analysis as randomized; and
(3) as taken directly from the definition of the ITT principle (see ICH E9 Glossary), that subjects should be followed up and assessed regardless of adherence to the planned course of treatment and that those assessments should be used in the analysis.

However, the question remains whether estimating an effect in accordance with the ITT principle always represents the treatment effect of greatest relevance to regulatory and clinical decision- making. The framework outlined in this addendum gives a basis for describing different treatment effects and some points to consider for the design and analysis of trials to give estimates of these treatment effects that are reliable for decision-making.

Question 4

Missing Data

(1) the addendum distinguishes ____ of randomized treatment from study ____ and
(2) the addendum highlights the distinct consequences of different ____.

2 important distinctions

Answer 4

(1) the addendum distinguishes discontinuation of randomized treatment from study withdrawal and
(2) the addendum highlights the distinct consequences of different intercurrent events.

Question 5

Missing Data vs Intercurrent Events, Examples

A subject switching treatments in an oncology trial: ____
A subject for whom no outcome event can be observed because the trial is completed: ____

Answer 5

A subject switching treatments in an oncology trial: Intercurrent Events (the clinical question of interest in respect to that event should be clear).
A subject for whom no outcome event can be observed because the trial is completed: Missing Data (administrative censoring that should be addressed in the statistical analysis)

Having clarity in the estimand gives a basis for planning which data should be collected and hence which data, when not collected, present a missing data problem to be addressed in the statistical analysis.

Question 6

Analysis Set, Amended Definition

Defined to be as close as possible to including ____ subjects, considering trials often include ____ on the same subject.

Answer 6

Defined to be as close as possible to including all randomized subjects, considering trials often include repeated measurements on the same subject.

Question 7

Sensitivity Analysis for Robustness

1. Sensitivity of ____ to the assumptions of a chosen method of analysis
2. Sensitivity to the choice of ____ more broadly

2 important distinctions

Answer 7

1. Sensitivity of inference to the assumptions of a chosen method of analysis
2. Sensitivity to the choice of analytic approach more broadly

Question 8

Sensitivity of Analytic Approach

With precise specification of an agreed-upon ____ and a ____ of analysis that is both aligned to the estimand and prespecified to a level of detail that it can be replicated precisely by a third party, regulatory interest can focus on sensitivity to deviations from ____ and limitations in the ____ in respect to a particular analysis.

Aim

Answer 8

With precise specification of an agreed-upon estimand and a method of analysis that is both aligned to the estimand and prespecified to a level of detail that it can be replicated precisely by a third party, regulatory interest can focus on sensitivity to deviations from assumptions and limitations in the data in respect to a particular analysis.

Question 9

Estimands

An estimand is a precise description of the ____ reflecting the clinical question posed by a given clinical trial objective.

The description of an estimand involves precise specifications of certain ____, which should be developed based not only on ____ but also on how ____ are reflected in the clinical question of interest.

Answer 9

An estimand is a precise description of the treatment effect reflecting the clinical question posed by a given clinical trial objective.

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.

Question 10

Strategies for Addressing Intercurrent Events

1. Treatment Policy Strategy: The occurrence of the intercurrent event is considered ____ in defining the treatment effect of interest; the values for the variable of interest are used ____ of whether the intercurrent event occurs. (ITT principle, except for terminal events)
2. Hypothetical Strategies: A scenario is ____ in which the intercurrent event would not occur: the value of the variable to reflect the clinical question of interest is the value that the variable ____ in the hypothetical scenario defined.
3. Composite Variable Strategies: This strategy relates to the ____ of interest. An intercurrent event is considered to be informative about the patient’s outcome and is therefore incorporated into the ____ of the variable.
4. While-on-Treatment Strategies: Response to treatment ____ the occurrence of the intercurrent event is of interest (while-on-treatment, or while alive)
5. Principal Stratum Strategies: This strategy relates to the ____ of interest. The clinical question of interest relates to the treatment effect only within the ____.

When selecting strategies, it might be important to distinguish between trials designed for superioity or equivalence/non-inferioiry.

Answer 10

1. Treatment Policy Strategy: The occurrence of the intercurrent event is considered irrelevant in defining the treatment effect of interest; the values for the variable of interest are used regardless of whether the intercurrent event occurs.
2. Hypothetical Strategies: A scenario is envisaged in which the intercurrent event would not occur: the value of the variable to reflect the clinical question of interest is the value that the variable would have taken in the hypothetical scenario defined.
3. Composite Variable Strategies: This strategy relates to the variable of interest. An intercurrent event is considered to be informative about the patient’s outcome and is therefore incorporated into the definition of the variable.
4. While-on-Treatment Strategies: Response to treatment before the occurrence of the intercurrent event is of interest (while-on-treatment, or while alive)
5. Principal Stratum Strategies: This strategy relates to the population of interest. The clinical question of interest relates to the treatment effect only within the principal stratum.

Question 11

Estimand Atributes

1. The ____ condition of interest
2. The ____ of patients targetd
3. The variable (____) to be obtained for each patient
4. Other ____ events reflected in treatment policy, hypotehetical or while-on treatment
5. A ____-level summary

Answer 11

1. The treatment condition of interest
2. The population of patients targetd
3. The variable (endpoint) to be obtained for each patient
4. Other intercurrent events reflected in treatment policy, hypotehetical or while-on treatment
5. A Population-level summary

Question 12

Considerations for Construction of Estimand

1. the ____ under study;
2. the clinical ____ (e.g., the availability of alternative treatments);
3. the ____ of treatment (e.g., one-off dosing, short-term treatment, or chronic dosing);
4. the ____ of treatment (e.g., prevention, disease modification, symptom control).
5. whether an estimate of the treatment effect can be ____ that is ____ for decision-making.

Answer 12

1. the disease under study;
2. the clinical context (e.g., the availability of alternative treatments);
3. the administration of treatment (e.g., one-off dosing, short-term treatment, or chronic dosing);
4. the goal of treatment (e.g., prevention, disease modification, symptom control).
5. whether an estimate of the treatment effect can be derived that is reliable for decision-making.

Question 13

Estimand

A precise description of the ____ reflecting the clinical question posed by the trial objective. It summarizes at a ____-level what the outcomes would be in the same patients under different treatment conditions being compared.

Answer 13

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 14

Estimate

A ____ value computed by an estimator.

Answer 14

A numerical value computed by an estimator.

Question 15

Estimator

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

Answer 15

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

Question 16

Intercurrent Events

Events occurring ____ treatment initiation that affect either the ____ or the ____ of the measurements associated with the clinical question of interest. Intercurrent events should be addressed when describing the clinical question of interest to precisely define the ____ that is to be estimated.

Answer 16

Events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question of interest. Intercurrent events should be addressed when describing the clinical question of interest to precisely define the treatment effect that is to be estimated.

Question 17

Missing Data

Data that ____ meaningful for the analysis of a given estimand but were not collected. They should be distinguished from data that ____ or data that are ____ considered meaningful because of an ____.

Answer 17

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 18

Principal Stratification

Classification of subjects according to the potential occurrence of an ____ on all treatments. With two treatments, there are ____ 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, and subjects who would experience the event on both treatments.

Answer 18

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, and subjects who would experience the event on both treatments.

Question 19

Principal Stratum

In this document, a principal stratum refers to any of the strata (or combination of strata) defined by ____.

Answer 19

In this document, a principal stratum refers to any of the strata (or combination of strata) defined by principal stratification.

Question 20

Sensitivity Analysis

A series of analyses conducted with the intent to explore the robustness of ____ from the main estimator to deviations from its underlying modeling ____ and limitations in the ____.

Answer 20

A series of analyses conducted with the intent to explore the robustness of inferences from the main estimator to deviations from its underlying modeling assumptions and limitations in the data.

Question 21

Supplementary Analysis

A general description for analyses that are conducted in addition to the main and sensitivity analysis with the intent to provide ____ insights into the understanding of the treatment effect.

Answer 21

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 22

Adverse Event (AE)

Clinical problem occurring ____ treatment including “diseases, signs and symptoms” typically investigated and documented with details such as type (serious or not), expectedness, relationship to treatment (e.g., onset at time of treatment, resolution upon stopping treatment and recurring when treatment restarts, etc.), toxicity grade (using a pre-specified grading scale which has been duly justified), treatment and duration of problem as well as final outcome. AEs are defined using a common adverse event dictionary and all are reported regardless of ____ to treatment unless specified otherwise in protocol.

Answer 22

Clinical problem occurring during treatment including “diseases, signs and symptoms” typically investigated and documented with details such as type (serious or not), expectedness, relationship to treatment (e.g., onset at time of treatment, resolution upon stopping treatment and recurring when treatment restarts, etc.), toxicity grade (using a pre-specified grading scale which has been duly justified), treatment and duration of problem as well as final outcome. AEs are defined using a common adverse event dictionary and all are reported regardless of relationship to treatment unless specified otherwise in protocol.

Question 23

Bias

“The ____ tendency of any factors associated with the design, conduct, analysis and interpretation of the results of clinical trials to make the estimate of a treatment effect ____ from its true value.”

Statistical principals are used in clinical trials in order to control bias by including activities like ____ and ____ .

Answer 23

“The systematic tendency of any factors associated with the design, conduct, analysis and interpretation of the results of clinical trials to make the estimate of a treatment effect deviate from its true value.”

Statistical principals are used in clinical trials in order to control bias by including activities like blinding and randomization.

Question 24

Estimand

A precise treatment ____ description corresponding to a clinical question in a clinical trial objective. This statistical construct requires a person to estimate the ____ expected in the same patients under the different treatment conditions proposed in the clinical trial. The process of creating an estimand includes careful consideration of ____ and ____.

Answer 24

A precise treatment effect description corresponding to a clinical question in a clinical trial objective. This statistical construct requires a person to estimate the clinical outcomes expected in the same patients under the different treatment conditions proposed in the clinical trial. The process of creating an estimand includes careful consideration of intercurrent events and sensitivity analyses.

Question 25

Intercurrent Events

Data about anything happening (after treatment starts) which might ____ with treatment effect measurements in the clinical trial. These potentially ____ data should be carefully considered when defining each clinical trial question so the treatment effect can be accurately estimated and measured for each clinical trial objective.

Answer 25

Data about anything happening (after treatment starts) which might interfere with treatment effect measurements in the clinical trial. These potentially confounding data should be carefully considered when defining each clinical trial question so the treatment effect can be accurately estimated and measured for each clinical trial objective.

Question 26

Missing Data

Uncollected measurements ____ in the clinical trial. Data which ____ (e.g., due to death of a study subject preventing future data collection) or data ____ (e.g., due to an intercurrent event where the patient requires a new treatment and then requires exclusion of future data from the clinical trial analysis) are ____ the same as missing data.

Answer 26

Uncollected measurements required in the clinical trial. Data which do not exist (e.g., due to death of a study subject preventing future data collection) or data without meaning (e.g., due to an intercurrent event where the patient requires a new treatment and then requires exclusion of future data from the clinical trial analysis) are not the same as missing data.

Question 27

Primary Analysis

Statistical evaluation of the ____ clinical trial study objective data as pre-specified in trial protocol. Note: “secondary” analyses are ____ and are often pre- specified to further understand data and to address potential data problems.

Answer 27

Statistical evaluation of the key clinical trial study objective data as pre-specified in trial protocol. Note: “secondary” analyses are supplemental and are often pre- specified to further understand data and to address potential data problems.

Question 28

Protocol

Written plan describing the required clinical trial activities and processes including, but not limited to, the purpose/____, ____ including data collection and statistical analyses, ____ rules, ____, roles of trial ____, ____ circumstances and subject ____. Changes to the protocol are documented in written protocol amendments.

Answer 28

Written plan describing the required clinical trial activities and processes including, but not limited to, the purpose/objectives, methods including data collection and statistical analyses, stopping rules, benefits and risks, roles of trial personnel, special circumstances and subject treatments. Changes to the protocol are documented in written protocol amendments.

Question 29

Robustness

A trial condition where the overall clinical trial conclusions are ____ impacted by the clinical trial assumptions, data limitations or statistical analysis methods used. A clinical trial is considered robust when the same treatment effects and overall clinical trial conclusions are consistently found ____ of the analytic methods chosen.

Answer 29

a trial condition where the overall clinical trial conclusions are NOT impacted by the clinical trial assumptions, data limitations or statistical analysis methods used. A clinical trial is considered robust when the same treatment effects and overall clinical trial conclusions are consistently found regardless of the analytic methods chosen.

Question 32

Sensitivity Analysis

Evaluations exploring all ____ measurements including all ____ from the underlying data assumptions and ____. The sensitivity analysis includes a pre-specified estimand, detail level and analysis method to ensure a third party can ____ the evaluation.

Answer 32

Evaluations exploring all treatment effect measurements including all deviations from the underlying data assumptions and limitations. The sensitivity analysis includes a pre-specified estimand, detail level and analysis method to ensure a third party can replicate the evaluation.