EFPIA / EFSPI Estimand Implementation Working Group (EIWG)
Charter & Purpose
“EIWG brings together statisticians and clinicians to support the estimand journey”
- To provide a cross-industry forum to:
- share Industry and Academic experiences of implementing the new estimand framework introduced in ICH E9(R1)
- discuss issues emerging through implementation
- be champions and engage in scientific discussion about the value and benefits of the framework
- With the aim to:
- give feedback and recommendations for best practices
- promote broad understanding and awareness of the framework within and outside of statistics
- consolidate issues and topics for discussion with the ICH E9 Implementation Working Group
Ongoing/planned Activities & Achievement
- Activities to raise awareness and promote the value:
- Training through case studies, e.g., through the EIWG Estimand Training Academy
- Present EIWG findings at scientific meetings/conferences
- Lead publications on key topics, e.g. estimation methods
- Communication plan highlighting emerging news and summary trends relating to ICH E9(R1) implementation
- Activities to provide recommendations on best practices:
- Develop best practices / recommendations e.g. incorporating estimands into protocols, reporting estimands
- Develop generic case studies to support implementation
- Explore implementation of estimands in non-confirmatory trials e.g. PKPD and non-interventional studies
- Outreach and collaboration with key stakeholder groups, e.g., TransCelerate, PhUSE, NIH
2022 EIWG Subteams
2022 Achievements - Training sub-team
The training committee has continued to work on webinars for their training series ‘EIWG Estimand Training Academy’ targeting anyone working in clinical trials.
All trainings provided so far are freely available as ‘Video-on-Demand’
Portal: https://psiweb.org/vod/Index/ or YouTube on the EFPIA channel
2022 Achievements - Estimation sub-team
Estimating the treatment-policy strategy with continuous data and incomplete post-IE follow-up is a relevant and under-researched issue. To address it, the group has assessed the performance of different estimators – based on either multiple imputation (MI) or mixed effect models (MMRM) – for simulated trials based on the HbA1c endpoint from the PIONEER1 study. The properties of the estimators (bias and variance shown here) generally confirm the equivalence of MI and MMRM approaches (if the same assumptions are made) and the particular importance of collecting post-IE data. The complex trade-off between variance inflation and accuracy needs to be carefully evaluated further.
2022 Achievements - Early Phase & Other Studies sub-team
This sub-team was created as a forum for both statisticians (industry & academia) and pharmacokinetics as well as regulators to help bridge the gap in the estimands framework with regards other study types including early phase and clinical pharmacology where the purpose is not confirmatory efficacy.
We presented a poster (Does the Estimand Framework Add Value to Clinical Pharmacology Trials?) at the PSI conference 2022. A manuscript is under preparation with focus on bioequivalence/bioavailability studies and is planned to be published in a clinical pharmacology journal in 2023.
The implementation of estimands in early phase studies (including dose finding and CRMs) are also being discussed within this workstream. We aim to share some of our work at the PSI conference in 2023.
2022 Achievements - Communications sub-team
In 2022 the homepage of the group was fully revised and summarizes all work of the EIWG.
Posters of the working group were presented at the 2022 PSI conference in Gothenburg and the 2022 Regulatory Industry workshop in Basel.
2022 Achievements - Estimands in non-inferiority trials sub-team
The ICH E9(R1) includes limited guidance in relation to non-inferiority (NI) trials. Current regulatory guidelines on NI trials predate the release of the addendum and the per protocol analysis set plays an important part in the EMA NI guidelines. In contrast, ICH E9(R1) questions the role of the per protocol set and this has led to confusion as regards to the applicability of the EMA Points to consider on switching between superiority and non-inferiority.
The sub-team is discussing which estimands can be considered relevant in an NI setting and how they fit into existing guidelines. The sub-team members are sharing recent regulatory feedback on NI trials, and we are discussing questions such as
- What is the underlying clinical question to be answered in an NI trial?
- Are two estimands with different strategies for intercurrent events required to reflect the spirit in the EMA Points to consider on switching between superiority and non-inferiority?
- Can protocol violations be handled as intercurrent events? Is there any remaining role for a Per Protocol analysis set?
- Can different estimands be used to show NI and superiority in the same trial (hierarchical set-up)?
- How does the estimand framework impact the choice of the NI margin?
The sub-team is planning to prepare a manuscripton these topics.
EIWG Estimand Training Academy
- Targeted to anyone working in clinical trials: Clinician, Regulator, Investigator, Academic, Ethics Committee, HTA Agencies, Statistician.
- All three trainings are freely available as ‘Video-on-Demand’
- A. Morga, NR. Latimer, M. Scott, N. Hawkins, M. Schlichting, J. Wang. Is Intention to Treat Still the Gold Standard or Should Health Technology Assessment Agencies Embrace a Broader Estimands Framework?: Insights and Perspectives From NICE and IQWiG on the ICH E9(R1) Addendum. Value Health. 2022 Sep 20:S1098-3015(22)02148-9. https://doi.org/10.1016/j.jval.2022.08.008
- H. Lynggaard, J. Bell, C. Lösch, A. Besseghir, K. Rantell, V. Schoder, V. Lanius. Principles and Recommendations for Incorporating Estimands into Clinical Study Protocol Templates. Trials (2022) https://doi.org/10.1186/s13063-022-06515-2
- C. Fletcher, N. Hefting, M. Wright, J. Bell, J. Anzures-Cabrera, D Wright, H. Lynggaard, A. Schueler. Marking 2-years of new thinking in clinical trials - the estimand journey. Ther Innov Regul Sci 56, 637–650 (2022). https://doi.org/10.1007/s43441-022-00402-3
- O. N. Keene, D. Wright, A. Phillips, M. Wright. Why ITT analysis is not always the answer for estimating treatment effects in clinical trials (2021). Contemporary Clinical Trials. https://doi.org/10.1016/j.cct.2021.106494
- D. Wright, H. Lynggaard , S. Englert, V. Lanius, O. Keene. Why Estimands are Needed to Define Treatment Effects in Clinical Trials. Submitted
Partnerships with related groups
- European special interest group “Estimands in oncology”, sponsored by PSI and EFSPI and ASA scientific working group of the ASA biopharmaceutical section
- Mission: The cross-industry working group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials.
- Liaison: Stefan Englert
- Mission: Sharing ideas, tools and standards around data, statistical and reporting technologies to advance the future of life sciences.
- Liaison: Armin Schueler
- Mission: TransCelerate BioPharma’s mission is to collaborate across the global biopharmaceutical research and development community to identify, prioritize, design, and facilitate the implementation of solutions designed to drive the efficient, effective and high-quality delivery of new medicines.
- Liaison: Pepa Polavieja and Helle Lynggaard
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