Aligning Estimators With Estimands in Clinical Trials: Putting the ICH E9(R1) Guidelines Into Practice

Mallinckrodt, Craig; Bell, J. Simon; Liu, G.; Ratitch, Bohdana; O’Kelly, Michael; Lipkovich, Ilya; Singh, Pritibha; Xu, Lei; Molenberghs, Geert

doi:10.1007/s43441-019-00063-9

Cited by 49 publications

(46 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, a sensitivity analysis will adjust for unequal observation time and use the difference in pain cumulated over 1 year between both treatment groups. Here, we follow the hypothetical estimand strategy for dealing with intercurrent events, wanting to know what outcomes would have been observed if patients had survived 1 year [ 29 ]. In this study, there are several types of intercurrent events (ICEs: like death, drop-out, toxicity), which stay in conflict with a standardized process for longitudinal measurements of pain over a fixed time period.…”

Section: Primary and Secondary Endpointsmentioning

confidence: 99%

MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC)

et al. 2022

View full text Add to dashboard Cite

Background Pain symptoms in the upper abdomen and back are prevalent in 80% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), where the current standard treatment is a systemic therapy consisting of at least doublet-chemotherapy for fit patients. Palliative low-dose radiotherapy is a well-established local treatment option but there is some evidence for a better and longer pain response after a dose-intensified radiotherapy of the primary pancreatic cancer (pPCa). Stereotactic body radiation therapy (SBRT) can deliver high radiation doses in few fractions, therefore reducing chemotherapy-free intervals. However, prospective data on pain control after SBRT of pPCa is very limited. Therefore, we aim to investigate the impact of SBRT on pain control in patients with mPDAC in a prospective trial. Methods This is a prospective, double-arm, randomized controlled, international multicenter study testing the added benefit of MR-guided adaptive SBRT of the pPca embedded between standard of care-chemotherapy (SoC-CT) cycles for pain control and prevention of pain in patients with mPDAC. 92 patients with histologically proven mPDAC and at least stable disease after initial 8 weeks of SoC-CT will be eligible for the trial and 1:1 randomized in 3 centers in Germany and Switzerland to either experimental arm A, receiving MR-guided SBRT of the pPCa with 5 × 6.6 Gy at 80% isodose with continuation of SoC-CT thereafter, or control arm B, continuing SoC-CT without SBRT. Daily MR-guided plan adaptation intents to achieve good target coverage, while simultaneously minimizing dose to organs at risk. Patients will be followed up for minimum 6 and maximum of 18 months. The primary endpoint of the study is the “mean cumulative pain index” rated every 4 weeks until death or end of study using numeric rating scale. Discussion An adequate long-term control of pain symptoms in patients with mPDAC is an unmet clinical need. Despite improvements in systemic treatment, local complications due to pPCa remain a clinical challenge. We hypothesize that patients with mPDAC will benefit from a local treatment of the pPCa by MR-guided SBRT in terms of a durable pain control with a simultaneously favorable safe toxicity profile translating into an improvement of quality-of-life. Trial registration German Registry for Clinical Trials (DRKS): DRKS00025801. Meanwhile the study is also registered at ClinicalTrials.gov with the Identifier: NCT05114213.

show abstract

Section: Primary and Secondary Endpointsmentioning

confidence: 99%

MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC)

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Common strategies aligned with a treatment effect following definitions of "while on treatment" (i.e., the net effect observed just, while patients are still on treatment), or even "hypothetical" (i.e., the expected effect should the ICE not occurred) ignore that an ICE actually occurred. Finally, other strategies are possible, but despite several statistical methods that have been proposed for handling ICEs in survival analyses [8], they are also based on assumptions, and it might be difficult to reach a general consensus on the optimal way for handling them. For these reasons, PFS is a more vulnerable endpoint compared to overall survival, which can easily be retrieved as well as objectively assessed regardless of any ICE under the "treatment policy" strategy.…”

Section: Progression-free Survival Is a Vulnerable Endpointmentioning

confidence: 99%

Are Quality of Randomized Clinical Trials and ESMO-Magnitude of Clinical Benefit Scale Two Sides of the Same Coin, to Grade Recommendations for Drug Approval?

Rodríguez

Espósito

Oliveres

et al. 2021

JCM

View full text Add to dashboard Cite

The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them are analyzed to support the recommendations. For this reason, there are different scales to quantify and evaluate the quality of RCTs and the magnitude of the clinical benefits of new drugs for treating solid tumors. In this review, we discuss the value of the progression-free survival (PFS) as an endpoint in RCTs and the concordance between it and the overall survival (OS) as a measure of the quality of clinical trial designs. We summarize and analyze the different scales to evaluate the clinical benefits of new drugs such as the The American Society of Clinical Oncology value framework (ASCO-VF-NHB16) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the concordance between them, focusing on metastatic colorectal cancer (mCRC). We propose several definitions that would help to evaluate the quality of RCT, the magnitude of clinical benefit and the appropriate approval of new drugs in oncology.

show abstract

“…Furthermore, the addendum frequently uses statistical terminology, including the word “estimand” itself, which reduces the document's appeal to nonstatisticians. In response to ICH E9(R1), there has been a proliferation of cross‐industry working groups, scientific papers, 6‐11 regulatory guidance documents 12‐14 and conference sessions on the topic of estimands, which is a clear recognition of their importance. However, most discussions have focused on issues associated with intercurrent events (ICEs; post‐randomisation changes of treatment or patient “state”) and the statistical consequences of the different approaches to handling them.…”

Section: Introductionmentioning

confidence: 99%

The detailed clinical objectives approach to designing clinical trials and choosing estimands

Bell¹,

Hamilton

Sailer

et al. 2021

Pharmaceutical Statistics

View full text Add to dashboard Cite

Objective setting is a necessary early step in the development of a clinical trial. ICH E9(R1) notes that the clinical objectives of a trial lead directly to the choice of estimands but barely discusses objectives themselves. Indeed, there is very little guidance anywhere in literature about objectives in clinical trials. This article identifies the substantial overlap between description of estimands and high quality definitions of objectives. It consequently shows that the estimand is decided by the precise choice of trial objective, and that therefore estimand decisions should be made at the objective level. The Detailed Clinical Objectives approach is proposed to support this. It emphasises clarity, specificity and a clinical focus when choosing and documenting objectives. Template text and examples are included to provide guidance on how it can be used in real trials. Finally, we describe objective‐driven trial design, emphasising how strong objective setting establishes an important foundation for rigorous trial design discussions, logistical and operational decision‐making during trial preparations, and clear communication of results and conclusions at the end of the trial. Highlighting the distinctions between objectives and estimands, we note how an objective‐based framework can build on the ICH E9(R1) estimand framework to address many of its unanswered questions.

show abstract

Aligning Estimators With Estimands in Clinical Trials: Putting the ICH E9(R1) Guidelines Into Practice

Cited by 49 publications

References 31 publications

MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC)

MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC)

Are Quality of Randomized Clinical Trials and ESMO-Magnitude of Clinical Benefit Scale Two Sides of the Same Coin, to Grade Recommendations for Drug Approval?

The detailed clinical objectives approach to designing clinical trials and choosing estimands

Contact Info

Product

Resources

About