Academic treatment optimization studies in oncology and internal medicine: a risk- and burden-adapted regulatory framework for the European Union

Summary: Academic treatment optimization studies (TOS) play an important role in determining how established and emerging treatments should be combined, sequenced, intensified, de-intensified, or otherwise optimized in routine clinical care. Unlike commercial clinical trials, which primarily support the development and regulatory approval of new medicinal products, academic TOS frequently address questions for which commercial incentives are limited. Such studies therefore contribute directly to the evidence base underlying clinical guidelines and health-care standards. A substantial proportion of academic TOS involves authorized medicinal products used outside the strict wording of their marketing authorization (label), but within evidence-supported clinical practice. Current European clinical-trial regulation does not always adequately reflect the distinction between the label of a medicinal product and the incremental risk and burden introduced by a particular treatment optimization strategy. Increasing administrative and regulatory requirements disproportionately affect investigator-initiated multicentre studies with limited resources. This article presents a policy perspective derived from the experience of investigators, clinical researchers and ethics committee members involved in academic clinical trials. We propose a risk- and burden-adapted regulatory approach for eligible academic TOS. The relevant reference point for assessing proportionality should be normal clinical care rather than the label alone. Evidence-supported TOS involving authorized medicinal products, particularly studies corresponding to OECD categories A and B1, should be considered for a risk-proportionate regulatory pathway when the proposed intervention introduces minimal additional risk and burden compared with normal clinical care. Selected OECD B2 studies could potentially qualify where additional evidence and expert assessment demonstrate similarly low incremental risk. The assessment should be performed on a trial-specific basis. Relevant standards of routine care should be defined by the respective medical societies in the field. Ethics committees, supported by physicians experienced in the relevant disease area, should assess incremental risk and burden. Monitoring, oversight and reporting requirements should likewise be risk-proportionate and prospectively justified in the trial protocol. The objective is not deregulation of academic clinical research but risk-proportionate regulation. A risk-adapted framework for academic TOS could strengthen investigator-initiated evidence generation, particularly for questions with limited commercial incentives, and improve the evidence base for optimizing routine clinical care in Europe.