In October 2014 the ICH Steering Committee endorsed a final Concept Paper with the goal of developing new regulatory guidance, suggested to be an Addendum to ICH E9, which promotes harmonised standards on the choice of estimands in clinical trials and an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data. An Expert Working Group sponsored by ICH has been established
to further develop the concept and is due to report findings in December
2015. Frank Bretz and Chrissie Fletcher are the EFPIA representatives on
the ICH E9(R1) Expert Working Group.
As a first step in developing the response from the European industry to any guidance issued by the ICH E9(R1) Expert Working Group, PSI/EFSPI held a 1-day workshop on estimands and sensitivity analyses in February 2015. A list of meeting attendees with affiliations is given in Appendix 1. Most participants recognised that they had not been aware of the word “estimand” - still less actually used it – before the report “The prevention and treatment of missing data in clinical trials” was published by the National Research Council in 2010. So one important aspect of this area in the next few years will be to communicate and educate both statisticians and non-statisticians in the concepts, terminology and consequences of the choice of estimands for a clinical trial. The estimand framework helps to distinguish between the target of estimation (estimand) and the method of estimation (estimator).An estimand reflects what is to be estimated to address the scientific question of interest posed by a trial.
It will be important to develop and publicise some simple but informative examples which can motivate all involved in clinical trials to become more focussed on the choice of estimands. For example two relevant classes of estimand are the ‘de jure’ estimand (“efficacy”) and the ‘de facto’ estimand (“effectiveness”).
” The efficacy is an ideal treatment effect that could have been reached if all patients had fully adhered or, in other words, the expected effect a patient may reach if he or she takes the medication as directed. Because of the lack of perfect adherence in practice, the efficacy cannot be observed. In contrast, effectiveness comprises treatment effects that occur when full adherence to treatment is lacking. Besides the sole benefit of the treatment, effectiveness also takes into account safety and tolerability issues.” (Leuchs et al, 2015). The discussion group noted that the positioning of this new document as an addendum to ICH E9 may give the impression that it is of interest only or primarily to statisticians. Yet the “Statement of the Perceived Problem” makes it clear that all concerned with clinical trials need to give this area further thought – “Incorrect choice of estimand and unclear definitions for estimands lead to problems in relation to trial design, conduct and analysis and introduce potential for inconsistencies in inference and decision making.” Although the die is cast, some members of the PSI/EFSPI discussion group felt that attaching the addendum to ICH E8 on “General Considerations For Clinical Trials” might have involved a broader leadership in making the changes in practice required. In particular E8 would benefit from the addition of a robust definition of the objectives of a study.
The group would position the estimand as a more detailed statement of the objective, formulated to address the scientific question of interest posed by the trial. It would therefore specify:
• a population of interest, e.g. the population defined by the target Summary of Product Characteristics (not to be confused with the analysis population);
• an endpoint of interest, i.e. a measurement at a specific timepoint, and
• a measure of the relevant effect of the intervention, taking into account the potential confounding due to post-randomisation events such as non-compliance, use of rescue medication or death. It was noted that while a study design follows from the objectives and estimands, feasibility aspects may result in a feedback loop to refine them. It was felt that clearly defined estimands will be needed to make regulatory claims and that each estimand involved would need to be linked back to objectives and the study design.
It was recognised that different stakeholders may be interested in different estimands, in particular distinguishing between regulatory approval and Health Technology Assessment. However any assumption that the former are more interested in efficacy estimands and the latter in effectiveness estimands is over-simplistic, as there is some evidence of regulators not finding ‘de jure’ estimands useful.
The ICH E9(R1) Concept Paper focuses equally on sensitivity analyses, but the discussion group spent less time in this area. We agreed with the Concept Paper that there is no clear framework for planning and executing sensitivity analyses and that this can lead to inconsistency in regulatory decision-making. The recent paper by Leuchs et al (2015) gives a useful distinction between the goals of internal and external validity for sensitivity analysis and this framework may form a useful foundation for further work.
While the group had differing opinions in certain areas, it was agreed that this is an important area for statisticians to be involved in as we aim to clarify the objectives and applicability of clinical trials. Attendees at the PSI conference will be able to take advantage of two sessions on this topic on the morning of Tuesday May 12th, including statistical leaders from both FDA and MHRA as well as industry and academia. In addition the discussion group has had a letter to the editor accepted commenting on the Leuchs paper and is exploring a separate publication of its own.David Morgan (Ipsen)
Reference:
International Conference on Harmonisation (2014) Final Concept Paper E9(R1):
Addendum to Statistical Principles for Clinical Trials. Geneva, Switzerland.
A-K Leuchs, J Zinserling, A Brandt, D Wirtz and N Benda (2015) Choosing
Appropriate Estimands in Clinical Trials. Therapeutic Innovation & Regulatory
Science
Appendix 1: List of meeting attendees and affiliations
Juan Abellan-Andres Gruenenthal
Soren Andersen Novo Nordisk
Frank Bretz Novartis
Chrissie Fletcher Amgen
Lesley France AstraZeneca
Andrew Garrett Quintiles
Ray Harris Eisai
Oliver Keene GlaxoSmithKline
Magnus Kjaer AstraZeneca
David Morgan Ipsen
Michael O’Kelly Quintiles
Alan Phillips Icon
James Roger Live Data
In October 2014 the ICH Steering Committee endorsed a final Concept Paper with the goal of developing new regulatory guidance, suggested to be an Addendum to ICH E9, which promotes harmonised standards on the choice of estimands in clinical trials and an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data. An Expert Working Group sponsored by ICH has been established
to further develop the concept and is due to report findings in December
2015. Frank Bretz and Chrissie Fletcher are the EFPIA representatives on
the ICH E9(R1) Expert Working Group.
As a first step in developing the response from the European industry to any guidance issued by the ICH E9(R1) Expert Working Group, PSI/EFSPI held a 1-day workshop on estimands and sensitivity analyses in February 2015. A list of meeting attendees with affiliations is given in Appendix 1. Most participants recognised that they had not been aware of the word “estimand” - still less actually used it – before the report “The prevention and treatment of missing data in clinical trials” was published by the National Research Council in 2010. So one important aspect of this area in the next few years will be to communicate and educate both statisticians and non-statisticians in the concepts, terminology and consequences of the choice of estimands for a clinical trial. The estimand framework helps to distinguish between the target of estimation (estimand) and the method of estimation (estimator).An estimand reflects what is to be estimated to address the scientific question of interest posed by a trial.
It will be important to develop and publicise some simple but informative examples which can motivate all involved in clinical trials to become more focussed on the choice of estimands. For example two relevant classes of estimand are the ‘de jure’ estimand (“efficacy”) and the ‘de facto’ estimand (“effectiveness”).
” The efficacy is an ideal treatment effect that could have been reached if all patients had fully adhered or, in other words, the expected effect a patient may reach if he or she takes the medication as directed. Because of the lack of perfect adherence in practice, the efficacy cannot be observed. In contrast, effectiveness comprises treatment effects that occur when full adherence to treatment is lacking. Besides the sole benefit of the treatment, effectiveness also takes into account safety and tolerability issues.” (Leuchs et al, 2015). The discussion group noted that the positioning of this new document as an addendum to ICH E9 may give the impression that it is of interest only or primarily to statisticians. Yet the “Statement of the Perceived Problem” makes it clear that all concerned with clinical trials need to give this area further thought – “Incorrect choice of estimand and unclear definitions for estimands lead to problems in relation to trial design, conduct and analysis and introduce potential for inconsistencies in inference and decision making.” Although the die is cast, some members of the PSI/EFSPI discussion group felt that attaching the addendum to ICH E8 on “General Considerations For Clinical Trials” might have involved a broader leadership in making the changes in practice required. In particular E8 would benefit from the addition of a robust definition of the objectives of a study.
The group would position the estimand as a more detailed statement of the objective, formulated to address the scientific question of interest posed by the trial. It would therefore specify:
• a population of interest, e.g. the population defined by the target Summary of Product Characteristics (not to be confused with the analysis population);
• an endpoint of interest, i.e. a measurement at a specific timepoint, and
• a measure of the relevant effect of the intervention, taking into account the potential confounding due to post-randomisation events such as non-compliance, use of rescue medication or death. It was noted that while a study design follows from the objectives and estimands, feasibility aspects may result in a feedback loop to refine them. It was felt that clearly defined estimands will be needed to make regulatory claims and that each estimand involved would need to be linked back to objectives and the study design.
It was recognised that different stakeholders may be interested in different estimands, in particular distinguishing between regulatory approval and Health Technology Assessment. However any assumption that the former are more interested in efficacy estimands and the latter in effectiveness estimands is over-simplistic, as there is some evidence of regulators not finding ‘de jure’ estimands useful.
The ICH E9(R1) Concept Paper focuses equally on sensitivity analyses, but the discussion group spent less time in this area. We agreed with the Concept Paper that there is no clear framework for planning and executing sensitivity analyses and that this can lead to inconsistency in regulatory decision-making. The recent paper by Leuchs et al (2015) gives a useful distinction between the goals of internal and external validity for sensitivity analysis and this framework may form a useful foundation for further work.
While the group had differing opinions in certain areas, it was agreed that this is an important area for statisticians to be involved in as we aim to clarify the objectives and applicability of clinical trials. Attendees at the PSI conference will be able to take advantage of two sessions on this topic on the morning of Tuesday May 12th, including statistical leaders from both FDA and MHRA as well as industry and academia. In addition the discussion group has had a letter to the editor accepted commenting on the Leuchs paper and is exploring a separate publication of its own.David Morgan (Ipsen)
Reference:
International Conference on Harmonisation (2014) Final Concept Paper E9(R1):
Addendum to Statistical Principles for Clinical Trials. Geneva, Switzerland.
A-K Leuchs, J Zinserling, A Brandt, D Wirtz and N Benda (2015) Choosing
Appropriate Estimands in Clinical Trials. Therapeutic Innovation & Regulatory
Science
Appendix 1: List of meeting attendees and affiliations
Juan Abellan-Andres Gruenenthal
Soren Andersen Novo Nordisk
Frank Bretz Novartis
Chrissie Fletcher Amgen
Lesley France AstraZeneca
Andrew Garrett Quintiles
Ray Harris Eisai
Oliver Keene GlaxoSmithKline
Magnus Kjaer AstraZeneca
David Morgan Ipsen
Michael O’Kelly Quintiles
Alan Phillips Icon
James Roger Live Data
In October 2014 the ICH Steering Committee endorsed a final Concept Paper with the goal of developing new regulatory guidance, suggested to be an Addendum to ICH E9, which promotes harmonised standards on the choice of estimands in clinical trials and an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data. An Expert Working Group sponsored by ICH has been established
to further develop the concept and is due to report findings in December
2015. Frank Bretz and Chrissie Fletcher are the EFPIA representatives on
the ICH E9(R1) Expert Working Group.
As a first step in developing the response from the European industry to any guidance issued by the ICH E9(R1) Expert Working Group, PSI/EFSPI held a 1-day workshop on estimands and sensitivity analyses in February 2015. A list of meeting attendees with affiliations is given in Appendix 1. Most participants recognised that they had not been aware of the word “estimand” - still less actually used it – before the report “The prevention and treatment of missing data in clinical trials” was published by the National Research Council in 2010. So one important aspect of this area in the next few years will be to communicate and educate both statisticians and non-statisticians in the concepts, terminology and consequences of the choice of estimands for a clinical trial. The estimand framework helps to distinguish between the target of estimation (estimand) and the method of estimation (estimator).An estimand reflects what is to be estimated to address the scientific question of interest posed by a trial.
It will be important to develop and publicise some simple but informative examples which can motivate all involved in clinical trials to become more focussed on the choice of estimands. For example two relevant classes of estimand are the ‘de jure’ estimand (“efficacy”) and the ‘de facto’ estimand (“effectiveness”).
” The efficacy is an ideal treatment effect that could have been reached if all patients had fully adhered or, in other words, the expected effect a patient may reach if he or she takes the medication as directed. Because of the lack of perfect adherence in practice, the efficacy cannot be observed. In contrast, effectiveness comprises treatment effects that occur when full adherence to treatment is lacking. Besides the sole benefit of the treatment, effectiveness also takes into account safety and tolerability issues.” (Leuchs et al, 2015). The discussion group noted that the positioning of this new document as an addendum to ICH E9 may give the impression that it is of interest only or primarily to statisticians. Yet the “Statement of the Perceived Problem” makes it clear that all concerned with clinical trials need to give this area further thought – “Incorrect choice of estimand and unclear definitions for estimands lead to problems in relation to trial design, conduct and analysis and introduce potential for inconsistencies in inference and decision making.” Although the die is cast, some members of the PSI/EFSPI discussion group felt that attaching the addendum to ICH E8 on “General Considerations For Clinical Trials” might have involved a broader leadership in making the changes in practice required. In particular E8 would benefit from the addition of a robust definition of the objectives of a study.
The group would position the estimand as a more detailed statement of the objective, formulated to address the scientific question of interest posed by the trial. It would therefore specify:
• a population of interest, e.g. the population defined by the target Summary of Product Characteristics (not to be confused with the analysis population);
• an endpoint of interest, i.e. a measurement at a specific timepoint, and
• a measure of the relevant effect of the intervention, taking into account the potential confounding due to post-randomisation events such as non-compliance, use of rescue medication or death. It was noted that while a study design follows from the objectives and estimands, feasibility aspects may result in a feedback loop to refine them. It was felt that clearly defined estimands will be needed to make regulatory claims and that each estimand involved would need to be linked back to objectives and the study design.
It was recognised that different stakeholders may be interested in different estimands, in particular distinguishing between regulatory approval and Health Technology Assessment. However any assumption that the former are more interested in efficacy estimands and the latter in effectiveness estimands is over-simplistic, as there is some evidence of regulators not finding ‘de jure’ estimands useful.
The ICH E9(R1) Concept Paper focuses equally on sensitivity analyses, but the discussion group spent less time in this area. We agreed with the Concept Paper that there is no clear framework for planning and executing sensitivity analyses and that this can lead to inconsistency in regulatory decision-making. The recent paper by Leuchs et al (2015) gives a useful distinction between the goals of internal and external validity for sensitivity analysis and this framework may form a useful foundation for further work.
While the group had differing opinions in certain areas, it was agreed that this is an important area for statisticians to be involved in as we aim to clarify the objectives and applicability of clinical trials. Attendees at the PSI conference will be able to take advantage of two sessions on this topic on the morning of Tuesday May 12th, including statistical leaders from both FDA and MHRA as well as industry and academia. In addition the discussion group has had a letter to the editor accepted commenting on the Leuchs paper and is exploring a separate publication of its own.David Morgan (Ipsen)
Reference:
International Conference on Harmonisation (2014) Final Concept Paper E9(R1):
Addendum to Statistical Principles for Clinical Trials. Geneva, Switzerland.
A-K Leuchs, J Zinserling, A Brandt, D Wirtz and N Benda (2015) Choosing
Appropriate Estimands in Clinical Trials. Therapeutic Innovation & Regulatory
Science
Appendix 1: List of meeting attendees and affiliations
Juan Abellan-Andres Gruenenthal
Soren Andersen Novo Nordisk
Frank Bretz Novartis
Chrissie Fletcher Amgen
Lesley France AstraZeneca
Andrew Garrett Quintiles
Ray Harris Eisai
Oliver Keene GlaxoSmithKline
Magnus Kjaer AstraZeneca
David Morgan Ipsen
Michael O’Kelly Quintiles
Alan Phillips Icon
James Roger Live Data
In October 2014 the ICH Steering Committee endorsed a final Concept Paper with the goal of developing new regulatory guidance, suggested to be an Addendum to ICH E9, which promotes harmonised standards on the choice of estimands in clinical trials and an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data. An Expert Working Group sponsored by ICH has been established
to further develop the concept and is due to report findings in December
2015. Frank Bretz and Chrissie Fletcher are the EFPIA representatives on
the ICH E9(R1) Expert Working Group.
As a first step in developing the response from the European industry to any guidance issued by the ICH E9(R1) Expert Working Group, PSI/EFSPI held a 1-day workshop on estimands and sensitivity analyses in February 2015. A list of meeting attendees with affiliations is given in Appendix 1. Most participants recognised that they had not been aware of the word “estimand” - still less actually used it – before the report “The prevention and treatment of missing data in clinical trials” was published by the National Research Council in 2010. So one important aspect of this area in the next few years will be to communicate and educate both statisticians and non-statisticians in the concepts, terminology and consequences of the choice of estimands for a clinical trial. The estimand framework helps to distinguish between the target of estimation (estimand) and the method of estimation (estimator).An estimand reflects what is to be estimated to address the scientific question of interest posed by a trial.
It will be important to develop and publicise some simple but informative examples which can motivate all involved in clinical trials to become more focussed on the choice of estimands. For example two relevant classes of estimand are the ‘de jure’ estimand (“efficacy”) and the ‘de facto’ estimand (“effectiveness”).
” The efficacy is an ideal treatment effect that could have been reached if all patients had fully adhered or, in other words, the expected effect a patient may reach if he or she takes the medication as directed. Because of the lack of perfect adherence in practice, the efficacy cannot be observed. In contrast, effectiveness comprises treatment effects that occur when full adherence to treatment is lacking. Besides the sole benefit of the treatment, effectiveness also takes into account safety and tolerability issues.” (Leuchs et al, 2015). The discussion group noted that the positioning of this new document as an addendum to ICH E9 may give the impression that it is of interest only or primarily to statisticians. Yet the “Statement of the Perceived Problem” makes it clear that all concerned with clinical trials need to give this area further thought – “Incorrect choice of estimand and unclear definitions for estimands lead to problems in relation to trial design, conduct and analysis and introduce potential for inconsistencies in inference and decision making.” Although the die is cast, some members of the PSI/EFSPI discussion group felt that attaching the addendum to ICH E8 on “General Considerations For Clinical Trials” might have involved a broader leadership in making the changes in practice required. In particular E8 would benefit from the addition of a robust definition of the objectives of a study.
The group would position the estimand as a more detailed statement of the objective, formulated to address the scientific question of interest posed by the trial. It would therefore specify:
• a population of interest, e.g. the population defined by the target Summary of Product Characteristics (not to be confused with the analysis population);
• an endpoint of interest, i.e. a measurement at a specific timepoint, and
• a measure of the relevant effect of the intervention, taking into account the potential confounding due to post-randomisation events such as non-compliance, use of rescue medication or death. It was noted that while a study design follows from the objectives and estimands, feasibility aspects may result in a feedback loop to refine them. It was felt that clearly defined estimands will be needed to make regulatory claims and that each estimand involved would need to be linked back to objectives and the study design.
It was recognised that different stakeholders may be interested in different estimands, in particular distinguishing between regulatory approval and Health Technology Assessment. However any assumption that the former are more interested in efficacy estimands and the latter in effectiveness estimands is over-simplistic, as there is some evidence of regulators not finding ‘de jure’ estimands useful.
The ICH E9(R1) Concept Paper focuses equally on sensitivity analyses, but the discussion group spent less time in this area. We agreed with the Concept Paper that there is no clear framework for planning and executing sensitivity analyses and that this can lead to inconsistency in regulatory decision-making. The recent paper by Leuchs et al (2015) gives a useful distinction between the goals of internal and external validity for sensitivity analysis and this framework may form a useful foundation for further work.
While the group had differing opinions in certain areas, it was agreed that this is an important area for statisticians to be involved in as we aim to clarify the objectives and applicability of clinical trials. Attendees at the PSI conference will be able to take advantage of two sessions on this topic on the morning of Tuesday May 12th, including statistical leaders from both FDA and MHRA as well as industry and academia. In addition the discussion group has had a letter to the editor accepted commenting on the Leuchs paper and is exploring a separate publication of its own.David Morgan (Ipsen)
Reference:
International Conference on Harmonisation (2014) Final Concept Paper E9(R1):
Addendum to Statistical Principles for Clinical Trials. Geneva, Switzerland.
A-K Leuchs, J Zinserling, A Brandt, D Wirtz and N Benda (2015) Choosing
Appropriate Estimands in Clinical Trials. Therapeutic Innovation & Regulatory
Science
Appendix 1: List of meeting attendees and affiliations
Juan Abellan-Andres Gruenenthal
Soren Andersen Novo Nordisk
Frank Bretz Novartis
Chrissie Fletcher Amgen
Lesley France AstraZeneca
Andrew Garrett Quintiles
Ray Harris Eisai
Oliver Keene GlaxoSmithKline
Magnus Kjaer AstraZeneca
David Morgan Ipsen
Michael O’Kelly Quintiles
Alan Phillips Icon
James Roger Live Data
In October 2014 the ICH Steering Committee endorsed a final Concept Paper with the goal of developing new regulatory guidance, suggested to be an Addendum to ICH E9, which promotes harmonised standards on the choice of estimands in clinical trials and an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data. An Expert Working Group sponsored by ICH has been established
to further develop the concept and is due to report findings in December
2015. Frank Bretz and Chrissie Fletcher are the EFPIA representatives on
the ICH E9(R1) Expert Working Group.
As a first step in developing the response from the European industry to any guidance issued by the ICH E9(R1) Expert Working Group, PSI/EFSPI held a 1-day workshop on estimands and sensitivity analyses in February 2015. A list of meeting attendees with affiliations is given in Appendix 1. Most participants recognised that they had not been aware of the word “estimand” - still less actually used it – before the report “The prevention and treatment of missing data in clinical trials” was published by the National Research Council in 2010. So one important aspect of this area in the next few years will be to communicate and educate both statisticians and non-statisticians in the concepts, terminology and consequences of the choice of estimands for a clinical trial. The estimand framework helps to distinguish between the target of estimation (estimand) and the method of estimation (estimator).An estimand reflects what is to be estimated to address the scientific question of interest posed by a trial.
It will be important to develop and publicise some simple but informative examples which can motivate all involved in clinical trials to become more focussed on the choice of estimands. For example two relevant classes of estimand are the ‘de jure’ estimand (“efficacy”) and the ‘de facto’ estimand (“effectiveness”).
” The efficacy is an ideal treatment effect that could have been reached if all patients had fully adhered or, in other words, the expected effect a patient may reach if he or she takes the medication as directed. Because of the lack of perfect adherence in practice, the efficacy cannot be observed. In contrast, effectiveness comprises treatment effects that occur when full adherence to treatment is lacking. Besides the sole benefit of the treatment, effectiveness also takes into account safety and tolerability issues.” (Leuchs et al, 2015). The discussion group noted that the positioning of this new document as an addendum to ICH E9 may give the impression that it is of interest only or primarily to statisticians. Yet the “Statement of the Perceived Problem” makes it clear that all concerned with clinical trials need to give this area further thought – “Incorrect choice of estimand and unclear definitions for estimands lead to problems in relation to trial design, conduct and analysis and introduce potential for inconsistencies in inference and decision making.” Although the die is cast, some members of the PSI/EFSPI discussion group felt that attaching the addendum to ICH E8 on “General Considerations For Clinical Trials” might have involved a broader leadership in making the changes in practice required. In particular E8 would benefit from the addition of a robust definition of the objectives of a study.
The group would position the estimand as a more detailed statement of the objective, formulated to address the scientific question of interest posed by the trial. It would therefore specify:
• a population of interest, e.g. the population defined by the target Summary of Product Characteristics (not to be confused with the analysis population);
• an endpoint of interest, i.e. a measurement at a specific timepoint, and
• a measure of the relevant effect of the intervention, taking into account the potential confounding due to post-randomisation events such as non-compliance, use of rescue medication or death. It was noted that while a study design follows from the objectives and estimands, feasibility aspects may result in a feedback loop to refine them. It was felt that clearly defined estimands will be needed to make regulatory claims and that each estimand involved would need to be linked back to objectives and the study design.
It was recognised that different stakeholders may be interested in different estimands, in particular distinguishing between regulatory approval and Health Technology Assessment. However any assumption that the former are more interested in efficacy estimands and the latter in effectiveness estimands is over-simplistic, as there is some evidence of regulators not finding ‘de jure’ estimands useful.
The ICH E9(R1) Concept Paper focuses equally on sensitivity analyses, but the discussion group spent less time in this area. We agreed with the Concept Paper that there is no clear framework for planning and executing sensitivity analyses and that this can lead to inconsistency in regulatory decision-making. The recent paper by Leuchs et al (2015) gives a useful distinction between the goals of internal and external validity for sensitivity analysis and this framework may form a useful foundation for further work.
While the group had differing opinions in certain areas, it was agreed that this is an important area for statisticians to be involved in as we aim to clarify the objectives and applicability of clinical trials. Attendees at the PSI conference will be able to take advantage of two sessions on this topic on the morning of Tuesday May 12th, including statistical leaders from both FDA and MHRA as well as industry and academia. In addition the discussion group has had a letter to the editor accepted commenting on the Leuchs paper and is exploring a separate publication of its own.David Morgan (Ipsen)
Reference:
International Conference on Harmonisation (2014) Final Concept Paper E9(R1):
Addendum to Statistical Principles for Clinical Trials. Geneva, Switzerland.
A-K Leuchs, J Zinserling, A Brandt, D Wirtz and N Benda (2015) Choosing
Appropriate Estimands in Clinical Trials. Therapeutic Innovation & Regulatory
Science
Appendix 1: List of meeting attendees and affiliations
Juan Abellan-Andres Gruenenthal
Soren Andersen Novo Nordisk
Frank Bretz Novartis
Chrissie Fletcher Amgen
Lesley France AstraZeneca
Andrew Garrett Quintiles
Ray Harris Eisai
Oliver Keene GlaxoSmithKline
Magnus Kjaer AstraZeneca
David Morgan Ipsen
Michael O’Kelly Quintiles
Alan Phillips Icon
James Roger Live Data
In October 2014 the ICH Steering Committee endorsed a final Concept Paper with the goal of developing new regulatory guidance, suggested to be an Addendum to ICH E9, which promotes harmonised standards on the choice of estimands in clinical trials and an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data. An Expert Working Group sponsored by ICH has been established
to further develop the concept and is due to report findings in December
2015. Frank Bretz and Chrissie Fletcher are the EFPIA representatives on
the ICH E9(R1) Expert Working Group.
As a first step in developing the response from the European industry to any guidance issued by the ICH E9(R1) Expert Working Group, PSI/EFSPI held a 1-day workshop on estimands and sensitivity analyses in February 2015. A list of meeting attendees with affiliations is given in Appendix 1. Most participants recognised that they had not been aware of the word “estimand” - still less actually used it – before the report “The prevention and treatment of missing data in clinical trials” was published by the National Research Council in 2010. So one important aspect of this area in the next few years will be to communicate and educate both statisticians and non-statisticians in the concepts, terminology and consequences of the choice of estimands for a clinical trial. The estimand framework helps to distinguish between the target of estimation (estimand) and the method of estimation (estimator).An estimand reflects what is to be estimated to address the scientific question of interest posed by a trial.
It will be important to develop and publicise some simple but informative examples which can motivate all involved in clinical trials to become more focussed on the choice of estimands. For example two relevant classes of estimand are the ‘de jure’ estimand (“efficacy”) and the ‘de facto’ estimand (“effectiveness”).
” The efficacy is an ideal treatment effect that could have been reached if all patients had fully adhered or, in other words, the expected effect a patient may reach if he or she takes the medication as directed. Because of the lack of perfect adherence in practice, the efficacy cannot be observed. In contrast, effectiveness comprises treatment effects that occur when full adherence to treatment is lacking. Besides the sole benefit of the treatment, effectiveness also takes into account safety and tolerability issues.” (Leuchs et al, 2015). The discussion group noted that the positioning of this new document as an addendum to ICH E9 may give the impression that it is of interest only or primarily to statisticians. Yet the “Statement of the Perceived Problem” makes it clear that all concerned with clinical trials need to give this area further thought – “Incorrect choice of estimand and unclear definitions for estimands lead to problems in relation to trial design, conduct and analysis and introduce potential for inconsistencies in inference and decision making.” Although the die is cast, some members of the PSI/EFSPI discussion group felt that attaching the addendum to ICH E8 on “General Considerations For Clinical Trials” might have involved a broader leadership in making the changes in practice required. In particular E8 would benefit from the addition of a robust definition of the objectives of a study.
The group would position the estimand as a more detailed statement of the objective, formulated to address the scientific question of interest posed by the trial. It would therefore specify:
• a population of interest, e.g. the population defined by the target Summary of Product Characteristics (not to be confused with the analysis population);
• an endpoint of interest, i.e. a measurement at a specific timepoint, and
• a measure of the relevant effect of the intervention, taking into account the potential confounding due to post-randomisation events such as non-compliance, use of rescue medication or death. It was noted that while a study design follows from the objectives and estimands, feasibility aspects may result in a feedback loop to refine them. It was felt that clearly defined estimands will be needed to make regulatory claims and that each estimand involved would need to be linked back to objectives and the study design.
It was recognised that different stakeholders may be interested in different estimands, in particular distinguishing between regulatory approval and Health Technology Assessment. However any assumption that the former are more interested in efficacy estimands and the latter in effectiveness estimands is over-simplistic, as there is some evidence of regulators not finding ‘de jure’ estimands useful.
The ICH E9(R1) Concept Paper focuses equally on sensitivity analyses, but the discussion group spent less time in this area. We agreed with the Concept Paper that there is no clear framework for planning and executing sensitivity analyses and that this can lead to inconsistency in regulatory decision-making. The recent paper by Leuchs et al (2015) gives a useful distinction between the goals of internal and external validity for sensitivity analysis and this framework may form a useful foundation for further work.
While the group had differing opinions in certain areas, it was agreed that this is an important area for statisticians to be involved in as we aim to clarify the objectives and applicability of clinical trials. Attendees at the PSI conference will be able to take advantage of two sessions on this topic on the morning of Tuesday May 12th, including statistical leaders from both FDA and MHRA as well as industry and academia. In addition the discussion group has had a letter to the editor accepted commenting on the Leuchs paper and is exploring a separate publication of its own.David Morgan (Ipsen)
Reference:
International Conference on Harmonisation (2014) Final Concept Paper E9(R1):
Addendum to Statistical Principles for Clinical Trials. Geneva, Switzerland.
A-K Leuchs, J Zinserling, A Brandt, D Wirtz and N Benda (2015) Choosing
Appropriate Estimands in Clinical Trials. Therapeutic Innovation & Regulatory
Science
Appendix 1: List of meeting attendees and affiliations
Juan Abellan-Andres Gruenenthal
Soren Andersen Novo Nordisk
Frank Bretz Novartis
Chrissie Fletcher Amgen
Lesley France AstraZeneca
Andrew Garrett Quintiles
Ray Harris Eisai
Oliver Keene GlaxoSmithKline
Magnus Kjaer AstraZeneca
David Morgan Ipsen
Michael O’Kelly Quintiles
Alan Phillips Icon
James Roger Live Data
Upcoming Events
PSI Training Course: Effective Leadership – the keys to growing your leadership capabilities
This course will consist of three online half-day workshops. The first will be aimed at building trust, the backbone of leadership and a key to becoming effective. This is key to building a solid foundation.
The second will be on improving communication as a technical leader. This workshop will focus on communication strategies for different stakeholders and will involve tips on effective communication and how to develop the skills of active listening, coaching and what improv can teach us about good communication.
The final workshop will bring these two components together to help leaders become more influential. This will also focus on how to use Steven Covey’s 7-Habits, in particular Habits 4, 5 and 6, which are called the habits of communication.
The workshops will be interactive, allowing you to practice the concepts discussed. There will be plenty of time for questions and discussion. There will also be reflective time where you can think about what you are learning and how you might experiment with it.
PSI Introduction to Industry Training (ITIT) Course - 2026/2027
An introductory course giving an overview of the pharmaceutical industry and the drug development process as a whole, aimed at those with 1-3 years' experience. It comprises of six 2-day sessions covering a range of topics including Research and Development, Toxicology, Data Management and the Role of a CRO, Clinical Trials, Reimbursement, and Marketing.
This networking event is aimed at statisticians that are new to the pharmaceutical industry who wish to meet colleagues from different companies and backgrounds.
This webinar brings together three bitesize complementary sessions to help PSI contributors create conference presentations and posters that communicate clearly and inclusively. Participants will explore how to refine their message, prepare materials effectively, and adopt practical habits that support confident, accessible delivery. A focused, supportive session designed to elevate every contribution.
Our monthly webinar series allows attendees to gain practical knowledge and skills in open-source coding and tools, with a focus on applications in the pharmaceutical industry. This month’s session, “Graphics Basics,” will introduce the fundamentals of producing graphics using the ggplot2 package.
Joint PSI/EFSPI Visualisation SIG 'Wonderful Wednesday' Webinars
Our monthly webinar explores examples of innovative data visualisations relevant to our day to day work. Each month a new dataset is provided from a clinical trial or other relevant example, and participants are invited to submit a graphic that communicates interesting and relevant characteristics of the data.
Join our Health Technology Assessment (HTA) European Special Interest Group (ESIG) for a webinar on the strategic role of statisticians in the Joint Clinical Assessment (JCA). The introduction of the JCA marks a new era for evidence generation and market access in Europe. As HTA requirements become more harmonized and methodologically demanding, the role of statisticians has evolved far beyond data analysis. Today, statistical expertise is central to shaping clinical development strategies, designing robust comparative evidence, and ensuring that submissions withstand the scrutiny of EU-level assessors. In this webinar, we explore how statisticians contribute strategically to successful JCA outcomes.
Statisticians in the Age of AI: On Route to Strategic Partnership
A 90-minute webinar featuring two case studies from Bayer and Roche demonstrating how statisticians successfully integrated into AI programs, followed by interactive discussion on strategies for elevating statistical expertise in the AI era.
This networking event is aimed at statisticians that are new to the pharmaceutical industry who wish to meet colleagues from different companies and backgrounds.
This networking event is aimed at statisticians that are new to the pharmaceutical industry who wish to meet colleagues from different companies and backgrounds.
This networking event is aimed at statisticians that are new to the pharmaceutical industry who wish to meet colleagues from different companies and backgrounds.
GSK - Statistics Director - Vaccines and Infectious Disease
We are seeking an experienced and visionary Statistics Director to join our Team and lead strategic statistical innovation across GSK’s Vaccines and Infectious Disease portfolio.
As a Senior Biostatistician I at ICON, you will play a pivotal role in designing and analyzing clinical trials, interpreting complex medical data, and contributing to the advancement of innovative treatments and therapies.
As a Statistical Scientist at ICON, you will play a pivotal role in designing and analyzing clinical trials, interpreting complex medical data, and contributing to the advancement of innovative treatments and therapies.
We have an exciting opportunity for an Associate Director, Biostatistics to join a passionate team within Advanced Quantitative Sciences – Full Development.
: We have an exciting opportunity for an Associate Director (AD), Statistical Programming, to join a passionate team within Advanced Quantitative Sciences- Development.
Novartis - Senior Principal Statistical Programmer
We have an exciting opportunity for a Senior Principal Statistical Programmer, to join a passionate team within Advanced Quantitative Sciences – Development.
Pierre Fabre - Clinical Development Safety Statistics Expert M/F
We are seeking a highly skilled and proactive Clinical Development Safety Statistics Expert to join our Biometry Department and the Biometry Leadership Team based in Toulouse (31, Oncopole) or Boulogne (92).
Pierre Fabre - Lead Statistician – Real World Evidence -CDI- M/F
Pierre Fabre Laboratories are hiring a highly skilled and experienced Lead Statistician – Real World Evidence (RWE) to join the Biometry Department, part of the Data Science & Biometry Department, based in Toulouse (Oncopôle) or Boulogne.
Pierre Fabre - Lead Statistician- Clinical Trials M/F
We are seeking a highly skilled and experienced Lead Statistician in Clinical Trials to join our Biometry Department based in Toulouse (31, Oncopole) or Boulogne (92).
We are looking for Senior Statistical Programmers in the UK to join Veramed, where you'll deliver high-impact programming solutions in an FSP-style capacity, while advancing your career in a supportive, growth-driven environment.
