Decentralized Clinical Trials: Scientific Considerations Through the Lens of the Estimand Framework.

While industry and regulators' interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient's experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site. This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions, and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimands.

Effectiveness of tisagenlecleucel versus real-world standard of care in relapsed/refractory follicular lymphoma.

Aim: To contextualize the effectiveness of tisagenlecleucel versus real-world standard of care (SoC) in relapsed/refractory follicular lymphoma. Materials & methods: A retrospective indirect matched comparison study using data from the phase II ELARA trial and the US Flatiron Health Research Database. Results: Complete response rate was 69.1 versus 17.7% and the overall response rate was 85.6 versus 58.1% in tisagenlecleucel versus SoC, post weighting by odds. For overall survival, an estimated reduction in the risk of death was observed in favor of tisagenlecleucel over SoC. The hazard ratio for progression-free survival was 0.45 (95% CI: 0.26, 0.88), and for time-to-next treatment was 0.34 (95% CI: 0.15, 0.78) with tisagenlecleucel versus SoC. Conclusion: A consistent trend toward improved efficacy end points was observed in favor of tisagenlecleucel versus SoC.

Indirect comparison of tisagenlecleucel and historical treatments for relapsed/refractory diffuse large B-cell lymphoma.

No head-to-head trials have compared the efficacy of tisagenlecleucel vs historical treatments for adults with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study indirectly compared the overall survival (OS) and overall response rate (ORR) associated with tisagenlecleucel, using data from the JULIET study (Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients; #NCT02445248), vs historical treatments assessed in the CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study follow-up population. To assess treatment effects in the treated (full analysis set [FAS]) and enrolled (intention-to-treat [ITT]) study populations, the JULIET FAS vs the CORAL follow-up FAS and JULIET ITT vs CORAL follow-up ITT populations were separately compared. Propensity score weighting using standardized mortality ratio weight (SMRW) and fine stratification weight (FSW) was used to compare OS and ORR, adjusting for baseline confounders. The results indicated that tisagenlecleucel was associated with a lower hazard of death among the FAS (adjusted hazard ratio [95% confidence interval], both FSW and SMRW, 0.44 [0.32, 0.59]) and ITT populations (FSW, 0.60 [0.44, 0.77]; SMRW, 0.57 [0.44, 0.73]; all, P < .001). Median OS was 12.48 months (JULIET) vs 4.34 to 4.40 months (CORAL) for the FAS, and 8.25 (JULIET) months vs 4.04 to 4.86 (CORAL) months for the ITT populations. Tisagenlecleucel was associated with a significantly higher ORR compared with historical treatments among the FAS (adjusted response rate difference [95% confidence interval], both FSW and SMRW, 36% [22%, 0.48%]; P < .001) and among the ITT populations after SMRW adjustment (11% [0%, 22%]; P = .043). This analysis supports that improved response and OS are achieved in patients with r/r DLBCL treated with tisagenlecleucel compared with those treated with alternative historical treatments.

Estimands for overall survival in clinical trials with treatment switching in oncology.

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention-to-treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment-policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross-industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation.

Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma.

BACKGROUND: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines. METHODS: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety. RESULTS: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events. CONCLUSIONS: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.).

Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neoplasms.

Spartalizumab, a humanized anti-programmed death protein 1 (PD-1) monoclonal antibody, was evaluated in patients with well-differentiated metastatic grade 1/2 neuroendocrine tumors (NET) and poorly-differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC). In this phase II, multicenter, single-arm study, patients received spartalizumab 400 mg every 4 weeks until confirmed disease progression or unacceptable toxicity. The primary endpoint was confirmed overall response rate (ORR) according to blinded independent review committee using response evaluation criteria in solid tumors 1.1. The study enrolled 95 patients in the NET group (30, 32 and 33 in the thoracic, gastrointestinal, and pancreatic cohorts, respectively), and 21 patients in the GEP-NEC group. The ORR was 7.4% (95% confidence interval [CI]: 3.0, 14.6) in the NET group (thoracic, 16.7%; gastrointestinal, 3.1%; pancreatic, 3.0%), which was below the predefined success criterion of ≥10%, and 4.8% (95% CI: 0.1, 23.8) in the GEP-NEC group. In the NET and GEP-NEC groups, the 12-month progression-free survival was 19.5% and 0%, respectively, and the 12-month overall survival was 73.5% and 19.1%, respectively. The ORR was higher in patients with ≥1% PD-L1 expression in immune/tumor cells or ≥1% CD8+ cells at baseline. The most common adverse events considered as spartalizumab-related included fatigue (29.5%) and nausea (10.5%) in the NET group, and increased aspartate and alanine aminotransferases (each 14.3%) in the GEP-NEC group. The efficacy of spartalizumab was limited in this heterogeneous and heavily pre-treated population; however, the results in the thoracic cohort is encouraging and warrants further investigation. Adverse events were manageable and consistent with previous experience.

Estimand framework: Are we asking the right questions? A case study in the solid tumor setting.

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.

What is an estimand & how does it relate to quantifying the effect of treatment on patient-reported quality of life outcomes in clinical trials?

BACKGROUND: Published in 2019, a new addendum to the ICH E9 guideline presents the estimand framework as a systematic approach to ensure alignment among clinical trial objectives, trial execution/conduct, statistical analyses, and interpretation of results. The use of the estimand framework for describing clinical trial objectives has yet to be extensively considered in the context of patient-reported outcomes (PROs). We discuss the application of the estimand framework to PRO objectives when designing clinical trials in the future, with a focus on PRO outcomes in oncology trial settings as our example. MAIN: We describe the components of an estimand and take a naïve PRO trial objective to illustrate how to apply attributes described in the estimand framework to inform construction of a detailed clinical trial objective and its related estimand. We discuss identifying potential post-randomization events that alter the interpretation of the endpoint or render its observation impossible (also defined as intercurrent events) in the context of PRO endpoints, and the implications of how to handle intercurrent events in the construction of the PRO objective. Using a simple objective statement, "What is the effect of treatment X on patient's quality of life?", we build up an example estimand statement and also use a previously published phase III oncology clinical trial to illustrate how an estimand for a PRO objective could have been written to align to the estimate framework. CONCLUSION: The use of the estimand framework, as described in the new ICH E9 (R1) addendum guideline will become a key common framework for developing clinical trial objectives for evaluating effects of treatment. In the context of considering PROs, the framework provides an opportunity to more precisely specify and build the rationale for patient-focused objectives. This will help to ensure that clinical trials used for registration are designed and analysed appropriately, enabling all stakeholders to accurately interpret conclusions about the treatment effects for patient-focused outcomes.

Assessing the Impact of COVID-19 on the Clinical Trial Objective and Analysis of Oncology Clinical Trials-Application of the Estimand Framework.

Abstract-Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for.

Estimands and the Patient Journey: Addressing the Right Question in Oncology Clinical Trials.

The diversity of patient journeys can raise fundamental questions regarding the evaluation of drug effects in clinical trials to inform clinical practice. When defining the treatment effect of interest in a trial, the researcher needs to account for events occurring after treatment initiation, such as the start of a new therapy, before observing the end point. We review the newly introduced estimand framework to structure discussions on the relationship between patient journeys and the treatment effect of interest in oncology trials. In 2017, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use released a draft addendum to its E9 guideline. The addendum introduces the concept of an estimand to precisely describe the treatment effect of interest. This estimand framework provides a structured approach to discuss how to account for intercurrent events that occur after random assignment and may affect the assessment or interpretation of the treatment effect. The framework is expected to improve coherence between trial objectives, design, analysis, and interpretation, as illustrated by examples in oncology disease settings. The estimand framework was applied to design a trial for a chimeric antigen receptor T-cell therapy. The treatment effect of interest was carefully defined considering the range of patient journeys expected for this particular indication and treatment. The trial design was developed accordingly to assess that treatment effect. All parties involved in the design of clinical trials need to consider possible patient journeys to define appropriate treatment effects and corresponding trial designs and analysis strategies. The estimand framework provides a common language to address the complexity introduced by varied patient journeys.

Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint. METHODS: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (±â€ˆ1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783. FINDINGS: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31). INTERPRETATION: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. FUNDING: Novartis Pharmaceuticals.