DOI: 10.6084/m9.figshare.26946324
title: End points in clinical trials in diffuse large B-cell lymphoma: time for more dialogue?

description: We observed lack of clarity and consistency in end point definitions of large randomized clinical trials in diffuse large B-cell lymphoma. These inconsistencies are such that trials might, in fact, address different clinical questions. They complicate interpretation of results, including comparisons across studies. Problems arise from different ways to account for events occurring after randomization including absence of improvement in disease status, treatment discontinuation or the initiation of new therapy. We call for more dialogue between stakeholders to define with clarity the questions of interest and corresponding end points. We illustrate that assessing different end point rules across a range of plausible patient journeys can be a powerful tool to facilitate such a discussion and contribute to better understanding of patient-relevant end points. This article talks about the lack of clarity and consistency in the definitions of outcomes used in clinical trials that investigate new treatments for diffuse large B-cell lymphoma. This is mainly due to how these different outcome definitions handle events such as absence of improvement in disease status, treatment discontinuation or initiation of new treatment. The authors discuss how these inconsistencies make it hard to interpret the results of individual clinical trials and to compare results across clinical trials. Defining the above events and consequently defining outcomes affects what we can learn from the trials and can lead to different results. Some approaches may not reflect good and bad outcomes for patients appropriately. This makes it challenging for patients, physicians, health authorities and payors to understand the true benefit of treatments under investigation and which one is better. This article serves as a call-to-action for more dialogue among all stakeholders involved in drug development and the decision-making process related to drug evaluations. There is an urgent need for clinical trials to be designed with more clarity and consistency on what is being measured so that relevant questions for patients and prescribing physicians are addressed. Understanding patient journeys will be key to successfully understand what truly matters to patients and how to measure the benefit of new treatments. Such discussions will contribute toward more clarity and consistency in the evaluation of new treatments. Time for more dialogue to harmonize end point definitions in lymphoma! Use patient journeys to bring more clarity, consistency and patient-relevance! Learn about key considerations for the choice of end points and why PFS is not always meaningful! End points in clinical trials should reflect good and bad outcomes for patients appropriately. Clarity on end point definitions is critical when interpreting trial results. Review of phase III trials in diffuse large B-cell lymphoma (DLBCL) highlights the prevailing lack of clarity and consistency in the choice of end points and their definitions. Combines the effect on survival of both the initial and any subsequent therapies received until death and captures potential effects of initial therapy on the choice, safety and efficacy of subsequent therapies. Challenging interpretation of clinical trial results in DLBCL with rapidly changing treatment options and multiple potentially curative subsequent treatments. The response of stable disease is a bad outcome for DLBCL patients, and as progression-free survival (PFS) does not count it as event it might not be patient-relevant. Different approaches to consider the impact of new therapies initiated prior to PFS event or to exclude their impact address different questions. Good understanding of the reasons for treatment discontinuations and start of new therapy critical to interpret PFS results. Event-free survival (EFS) considers not only death and progression as events, but also a type of ‘treatment failure’. Treatment discontinuation generally not used in confirmatory trials as 'treatment failure’ event as it can be influenced by other factors not related to efficacy. Start of new therapy often considered as treatment failure event regardless of the reason, i.e., even if it follows discontinuation due to toxicities. In some trials, start of a new therapy for efficacy-related reasons is defined as an event, showing a focus on the anti-tumour activity of the drug. Additional considerations required for studies of treatment strategies with multiple interventions such as CAR-T or transplant strategies. Challenging to interpret the results in the absence of clear, well-defined research objectives. When defining research objectives, it is important to differentiate between short-term and long-term effects and to consider duration of treatment, frequency of patient-reported outcomes (PRO) assessments, the impact of new therapies and deaths and whether quality of life (QoL) at later timepoints reflects only the results in responding patients. Various elements of patient journey, disease setting and therapy type impact the appropriateness of end points. Dialogue between all stakeholders needed to define more explicitly the questions of interest and corresponding end points in DLBCL and to ensure that relevant data are collected, clinical trials are designed to address these questions and the results are easier to interpret.