Patient-centered and proportionate safety reporting in clinical trials facilitates evidence-based medicine for the benefit of patients and society: An EHA priority

Abstract

The treatment landscape of hematologic malignancies is changing with a shift away from chemo- and radiotherapy towards targeted approaches and immunotherapies.¹ These novel treatment strategies often result in longer survival and, in some cases, have turned cancers with historically dismal outcomes into chronic or even curable disease.^{2, 3} However, comprehensive characterization of distinct side effect profiles in clinically meaningful ways remains a major challenge. There are many relevant stakeholders with an interest in safety reporting, and diverging perceptions of importance can create tensions between patients, clinicians, investigators, commercial sponsors, and regulatory authorities.⁴ Clinical research, including interventional clinical trials (CTs), is a key factor in ensuring patient safety through establishing evidence-based treatments that truly benefit patients. The European Hematology Association (EHA) has championed several activities to promote better safety reporting with less administrative burden in CTs. Herein, we summarize current initiatives and perspectives to modernize the assessment and reporting of treatment tolerability in hematologic malignancies.

Since its foundation and first position paper in 2018,⁵ The Lancet Haematology (TLH) Commission on Adverse Event (AE) Reporting has advocated for improving how tolerability of treatment is measured and reported. This international, multistakeholder consortium asserts that evaluation of treatment-related toxicity should go beyond reporting of maximum grade toxicities, currently the standard approach by which key safety data are presented in scientific communications. The Commission includes patient advocates, clinicians, clinical investigators, biostatistician, pharmacists, and multiple regulatory agency representatives. The first position papers were presented in an event at the EHA annual congress in 2018 with a follow-up to monitor progress in 2022. In the 2025 update,⁶ the authors provided an actionable framework to substantially improve and harmonize how toxicities are collected, analyzed, and reported. Specifically, they advocate for a more comprehensive depiction of longitudinal toxicity trajectories, improved visualization, implementation of interactive dashboards to explore tolerability data, and increasing use of patient-reported outcomes (PROs),^{7, 8} including in early-phase trials and throughout the regulatory process. Drawing on our growing knowledge of the toxicity patterns associated with novel therapies, the authors additionally propose a practical framework to enhance the evaluation, reporting, and interpretation of treatment tolerability in the context of targeted and immunotherapies.⁹ Thereby, the TLH AE Commission aims to put patients first and outlines pragmatic steps to revise our approach to measuring tolerability, a construct that reflects how patients feel and function on treatment. Striving for health equity on a global scale, there remain substantial challenges in low- and middle-income countries which may be addressed through infrastructure development, human resources training including integration of ancillary specialists and adaptation of global guidelines to local realities.¹⁰

The coalition for reducing bureaucracy in clinical trials (RBinCT) is a cross-disciplinary coalition of medical societies and patient advocates, where EHA has played a central role in fostering alignment between stakeholders.¹¹ The RBinCT campaign has advocated for substantial changes in safety reporting. When clinicians become investigators for commercial sponsors, the safety communication needs to be streamlined and efficient to secure what it is meant for—patient safety. Currently, an excess of safety reports is communicated directly to investigators without prior evaluation of novelty, importance, or consequences for patient management. As such, signals may be lost in the noise of excessive, unhelpful reporting. EHA believes that safety reports communicated to investigators should be aggregated and analyzed for consequences so that sponsors can advise on meaningful actions needed from the investigators. When sponsors feel unqualified to take such responsibility, evaluation of clinical importance and actions could be discussed with coordinating investigators and/or data safety monitoring boards. Cases of critical safety issues resulting in immediate clinical actions or communications to patients on substantially changed benefit/risk should still be provided to investigators directly in non-aggregated forms. We believe that reducing information overload will lead to better safety by enabling investigators to focus on essential reporting. Another focus is safety reporting in investigator-initiated CT in which authorized medicines are used in new combinations or dosing regimens. Full safety reporting currently entails CRF registration of all AEs and is time consuming as well as costly. While comprehensive safety data are indisputably important when investigational new drugs are tested, new treatment schedules, for example, treatment holidays for drugs with a well-established safety profile, will likely not generate new safety signals. The same could be the case for combinations of authorized drugs where pharmacodynamic or pharmacokinetic interactions are unlikely. In these instances, fit-for-purpose safety reporting includes reporting of only SUSARS to authorities and annual reporting of other SAEs, including protocol-defined exemption of well-established SAEs. Such a framework has already been implemented by the Danish Medicines Agency¹² and is aligned with EU legislation (Article 41 of the EU CTR, 536/2014). Risk-based approaches are also promoted by the most recent ICH E6 R3 guideline.¹³ What we need now is clear, harmonized EU guidance on how and when to use proportionate safety reporting. Academic sponsors should be guided by regulators in this process. In rare cases, a reduction in safety reporting can result in missed safety signals, but the administrative burden associated with CTs today, in part due to extensive safety reporting,¹⁴ limits our ability to establish evidence-based practice. This can have negative consequences not only for patients in the form of inferior treatments but also for our health care system through financial waste and ineffective resource use. Risk-proportionate safety reporting is not a panacea; it is a temporary repair of a dysfunctional system. As also proposed by the TLH AE Commission,⁹ future solutions include comprehensive, automized data capture from electronic health care records developed in close collaboration between commercial sponsors, clinicians, and hospital administrations.

EHA is also involved in other activities focusing on improving the EU CT ecosystem, which include discussions on safety reporting practices. The Cancer Medicines Forum (CMF) is a forum co-led by the European Medicines Agency (EMA) and the European Organization for Research and Treatment of Cancer (EORTC). The CMF is aligned with the EMA Regulatory Science to 2025 strategy, where focus areas include the development of network-led partnerships with academia for research in regulatory science.¹⁵ EHA actively takes part in the CMF meetings, and while meetings are closed, minutes are publicly available. Evidence generation through pragmatic trials embedded in clinical practice is a core theme. Such trials should be cost-effective and conductible within the budgets typically available to academic sponsors. Pragmatic trials have an important role in addressing scientific questions in areas where there are no economic incentives for commercial sponsors. Examples include dose optimization of authorized products, in particular dose de-escalations or treatment holidays for medicines typically prescribed until progression or unacceptable toxicity.⁹ Success is contingent on implementation of pragmatic safety monitoring to reduce costs and enable true integration in routine practice. From a conceptual standpoint, dose de-escalation trials should not result in new safety risks, and we believe that only SUSARs should be recorded. If the safety profile of new dosing is an important endpoint, more extensive capture of safety data should be tailored specifically to this endpoint; however, the value of annual safety reporting to authorities is debatable. Events related to inferior efficacy in exposure-de-escalation trials should not be communicated through safety reports but monitored closely by independent data monitoring committees and through interim analyses for futility.

Another key activity for EHA is the Accelerating Clinical Trials EU (ACT-EU) framework, an initiative launched by the EU Commission, EMA, and Heads of Medicines Agencies aimed at creating a better environment for clinical research and life science in the EU. An important part of the ACT-EU is the aspiration to involve relevant stakeholders in overseeing the ACT-EU program and advising on key priorities. This has been formalized in the multistakeholder platform (MSP) initiative, in which EHA is among the few European medical societies permanently represented. In this work, EHA has consistently supported and raised awareness of the importance of risk-proportionate safety reporting, activities that educate and support academic investigators in navigating the complexities of CTR, and more harmonized evaluation of CT in the EU to support multicountry CT. The latter is important for rare disease specialties like hematology, where effective international collaboration is critical.

From a patient perspective, it is crucial to more appropriately address the full complexities of toxicity in cancer treatment. Importantly, patient-reported and clinician-reported toxicity cannot be separated from quality of life. The “triangle of patient reality” links toxicity, quality of life, and patient preferences to guide research and clinical decisions. Patients' advocates involved in EHA activities have stressed that tolerability is not only a clinical judgment, but a deeply personal experience shaped by values and risk-benefit assessments made by patients. During the 2025 EHA-EMA session, the conversation highlighted that not all toxicities should be weighted similarly. Their impact may depend on incidence and worst grade, but duration, recurrence, and chronicity are equally important aspects. For example, a transient Grade 3–4 diarrhea for a few days would be more acceptable to most persons than chronic Grade 2 diarrhea for months to years. Echoing the conclusions of the TLH AE Commission, participants stressed that current safety reporting does not sufficiently capture these aspects, which preclude the use of “triangle of patient reality” concepts.

Concerns were also raised about safety reporting being limited to clinician-reported toxicity. Even when PROs are collected, they are often neglected and not used with its full potential to evaluate treatment tolerability. Moreover, infrequent reporting intervals limit understanding of the fluctuation of symptoms and lived experience. Therefore, our understanding of how toxicities develop, evolve, and impact the lives of patients remains poorly understood. With the limited duration of CT and selected patient populations enrolled, our understanding of toxicities in heterogeneous real-world population and how AEs impact survivorship on the long term is also limited, and such information is included in structured ways during discussions about treatment options. In particular, the patient representative shared the highly problematic experiences where chronic toxicities—for example, fatigue, neuropathy, and infertility—are not even linked to treatments given years before and a lack of ownership for collecting and linking long-term health problems to specific treatments. The reason is complex, but likely a lack of financial incentives, absence of systems for patients' self-reporting, and poor collaboration between hematologists, medical specialists managing specific late toxicities, and general practitioners play a role in making unique and specific toxicities experienced by patients difficult to recognize and correctly identify as treatment-related effects. This gap underscores the necessity of a profound change in how toxicity is understood, tracked, reported, and acted upon across the continuum of care. Tolerability measurement schemes and endpoints need to be revisited not only to improve research but also to better inform regulatory decisions and, in the end, clinical practice, so that toxicity, impact on daily functioning, and quality of life become more visible aspects of treatment decision-making. There was a broad consensus that truly modernizing safety reporting demands more space for the patient voice and patient engagement. For example, low-grade AEs could be captured mainly via systematic collection of patient-reported toxicity and their importance of patients' lives assessed via PRO questionnaires.

During the 2025 annual EHA congress, EHA partnered with EMA for a joint session on modernizing tolerability assessment and safety reporting. Most stakeholders with an interest in CT safety reporting were represented, including regulatory authorities (EMA), industry representatives, academic sponsors, clinicians, and—importantly—patient advocates. The session included short presentations and a lively panel discussion, which was dominated by some of the key topics outlined in the perspective. Importantly, this paper solely reflects the EHA and the academic/patient representatives' perspectives. However, we believe that relevant stakeholders share the same ambitions and are willing to work together for progress.

While EHA advocates for more flexible safety reporting and more innovative, patient-centric evaluation of safety data from CTs, it is important to emphasize that other stakeholders may have different views reflecting legal frameworks in place. Nevertheless, we believe that there was a general agreement on the necessity of modernizing the reporting of safety data, the incorporation of PROs, and reducing the administrative burden associated with safety reporting. All changes should be built on the lived experiences of patients whenever possible. While an organization like EHA has no formal power to directly change safety reporting mandated by regulatory authorities or installed by commercial sponsors, EHA and our members can have a profound influence on future safety reporting. Through continued active engagement in stakeholder activities, we can have an impact on policies by increasing awareness of the obstacles hematologists face and their potential solutions. Collective input from clinicians and investigators with first-hand experience through EHA is more critical than ever for making EU a leading continent for CTs again. As individual hematologists, we also have substantial influence through multiple channels. As investigators on CTs, we can advise on the collection of meaningful safety data, and we can explore emerging safety issues in a clinical perspective. As (co)authors or as reviewers of scientific manuscripts reporting CTs, we can request more clinically relevant safety reporting and meaningful analyses of collected safety data, including correlations with quality of life, duration of AEs, and AEs associated with discontinuations and dose-reductions.¹

Inspired by the engaging and thought-provoking exchange at the EHA-EMA session on safety reporting, we urge all stakeholders involved to continue in an open dialogue and collaboration towards making more meaningful assessments of treatment tolerability in hematologic malignancies. A famous Churchill quote reflects our situation very precisely “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” This session and other EHA activities represent crucial first steps into the direction of reversing the current decline of clinical research in the EU, but there is much important work still ahead of us.

Tarec Christoffer El-Galaly: Conceptualization; writing—original draft. Ananda Plate: Writing—review and editing. Gita Thanarajasingam: Writing—review and editing. Robin Doeswijk: Writing—review and editing. Martin Dreyling: Writing—review and editing. Paul J. Bröckelmann: Writing—original draft; conceptualization.

M.D. is an advisor to AbbVie, AstraZeneca, AvenCell, Beigene, BMS, Genmab, Gilead/Kite, Incyte, Janssen, Lilly/Loxo, Novartis, Roche, and Sobi; reports speakers honoraria from AstraZeneca, Beigene, BMS, Gilead/Kite, Janssen, Lilly, and Roche; and research support from AbbVie (inst), Gilead/Kite (inst), Janssen (inst), Lilly (inst), and Roche (inst). P.J.B. is an advisor or consultant for Hexal, Merck Sharp & Dohme (MSD), Need Inc., Stemline, and Takeda; holds stock options in Need Inc.; has received honoraria from AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene (BMS), Eli Lilly, MSD, Need Inc., Stemline, and Takeda; and reports research funding from BeiGene (inst), BMS (inst), MSD (inst), and Takeda (inst). All other authors do not declare any potential COI.

This research received no funding. PJB is supported through an Excellence Stipend from the Else Kröner Fresenius Founation (EKFS).