The authors’ argument rests on a distinction that is easy to state but has been largely ignored by regulators. Commercial trials sponsored by pharmaceutical companies exist to establish the efficacy and safety of new drugs for market authorization. Academic treatment optimization studies, or TOS, ask a fundamentally different question: how should treatments already available in the clinic be dosed, sequenced, combined, intensified, or de-escalated? These questions carry limited commercial incentive, yet they determine whether a new agent actually improves survival in routine care. Without academic trials systematically comparing treatment strategies against established standards, the field loses its capacity to translate scientific advances into better outcomes for patients.

The historical record shows what is at stake. In pediatric oncology, successive generations of randomized optimization trials conducted by cooperative study groups helped raise event-free survival for major childhood malignancies from below 20 percent in the 1950s to more than 60 percent, and for some diseases approximately 90 percent, by the early 2000s. Similar investigator-initiated randomized research established adjuvant chemotherapy for node-positive breast cancer and shaped multimodal treatment across leukemia, lymphoma, germ-cell tumors, colorectal cancer, and lung cancer. Comparable optimization questions have driven progress in cardiology and nephrology, where trials clarified how combinations of established therapies should be sequenced and intensified. These achievements were not the product of a single breakthrough drug but of iterative, comparative, and often unglamorous clinical experimentation.

The regulatory turning point came with the EU Clinical Trials Directive 2001/20, which introduced harmonized requirements for trial authorization, sponsor responsibilities, monitoring, safety reporting, and documentation. For industry-sponsored programs with dedicated infrastructure, the burden was absorbable. For investigator-initiated studies run on limited academic funding, it proved crushing. Berdel and colleagues illustrate the shift with data from the German Society for Paediatric Oncology and Haematology: the number of open treatment optimization studies fell from 33 in 2002 to just 2 in 2017. Over the same period, drug trials conducted under the directive increased and disease-oriented registries multiplied from 1 to 28. Registries can document real-world care and support quality improvement, but they cannot generate the randomized comparative evidence needed to establish which treatment strategy is superior.

The financial and temporal dimensions of the burden are documented in striking detail. Drawing on the personal experience of one author, the authors report that a monocenter Phase I trial that once took roughly one month from protocol to first patient visit now takes more than a year and a half, and more than four years from protocol to publication. A multicenter Phase II or III study that previously required three months to open now takes more than two years. Costs tell a similar story: a Phase I monocenter study that cost approximately 30,000 euros now exceeds 200,000 euros, while a Phase II/III multicenter trial has risen from under 50,000 euros to roughly 500,000 euros. Documentation has ballooned from around 100 pages to more than 3,000 pages for a single-center Phase I study, and from about 200 pages to over 3,000 pages for multicenter trials. The authors emphasize these are illustrative approximations rather than a systematic regulatory audit, but the magnitude of change is difficult to dismiss.

Data from beyond oncology reinforce the pattern. Between 2006 and 2012, the Ethics Committee of Westphalia-Lippe in Germany recorded a decline in investigator-initiated academic drug trials from 6 to 2, while commercial drug trials fell only modestly from 38 to 29 and registries increased from 1 to 11. The concurrent rise of registry-based activity and fall of interventional academic studies is consistent with a shift toward observational approaches as regulatory requirements intensified, a trend also reported from other EU member states. The authors acknowledge that such descriptive data cannot establish simple causality, and that growing collaboration between academia and industry complicates the interpretation of trial counts, but the structural shift in who initiates interventional research is difficult to ignore.

The Clinical Trials Regulation 536/2014, which replaced the directive and became mandatory for all EU and EEA trials since 31 January 2025, brought genuine improvements: a harmonized framework, a single submission portal through the Clinical Trials Information System, coordinated assessment, and increased transparency. Yet the authors argue that harmonization does not automatically produce risk-proportionality. Investigator-initiated multicenter studies still face substantial administrative hurdles, particularly when they involve complex treatment strategies, multiple interventions, or off-label use of authorized medicines. The relevant provisions are fragmented across the regulation’s text and difficult for investigators to navigate. Recent analyses continue to identify challenges for academic and pragmatic trials, and European policy documents, including the Draghi report on competitiveness, have raised concerns about the EU’s attractiveness as a location for clinical research.

The core of the authors’ proposal is a conceptual reframing: regulatory burden should be calibrated not to the marketing authorization status of a medicine but to the incremental risk and burden a specific research intervention introduces relative to established clinical care. The OECD classification distinguishes trials involving authorized medicines used within the label (category A), off-label use supported by published evidence or established practice (B1), off-label use without such support (B2), and non-authorized products (C). Many academic optimization studies fall into categories B1 and B2. An evidence-supported change in dose, duration, sequence, or combination of established treatments may carry little additional risk compared with routine care, even when technically off-label. Conversely, an intervention formally within a label may still introduce meaningful risk in a substantially different treatment context. The authors propose that OECD category A and B1 studies with minimal incremental risk should be eligible for a proportionate regulatory pathway, with selected B2 studies considered where additional evidence and expert assessment support a similarly low-risk classification.

Under this framework, such trials would still be registered through the Clinical Trials Information System to preserve transparency and harmonization, but would be assessed by ethics committees rather than necessarily by national competent authorities. Ethics committees, drawing on physicians experienced in the relevant disease area, would evaluate incremental risk on a trial-specific basis using predefined criteria. The definition of established clinical care would not rest with individual investigators but with medical societies, such as the European Society for Medical Oncology, which maintain regularly updated evidence-based guidelines across most cancer types. Monitoring, adverse-event reporting, and oversight would be risk-adapted, drawing on guidance developed by the Danish Medicines Agency, with every monitoring and reporting requirement justified prospectively in the protocol. The authors stress this does not mean less protection for participants; it means resources are directed toward risks that actually matter to participants and data integrity.

The proposal arrives at a politically opportune moment. In December 2025, the European Commission presented a draft European Biotech Act that includes measures to simplify clinical-trial procedures, reduce administrative burden, and accelerate authorization, including amendments to the Clinical Trials Regulation and further risk-based differentiation, with a new minimal-intervention category for OECD category A trials. The authors argue this movement should be extended to explicitly cover evidence-supported academic optimization studies, including OECD B1 and selected B2 trials. They acknowledge real challenges: definitions of established care may differ between countries, professional guidelines may lag behind rapidly evolving evidence, and ethics committees may initially apply different thresholds for minimal risk. These difficulties, they contend, argue for transparent criteria and shared guidance rather than abandoning risk-adapted assessment. The objective, as the authors and a broader coalition of European medical societies have emphasized, is not deregulation of academic clinical research but risk-proportionate regulation that preserves participant protection while restoring the capacity of independent investigators to answer the questions that industry has no incentive to ask.

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

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

Article References: Berdel, W. E., Dreyling, M., Schrappe, M., Wanner, C., & Schmidt, G. (2026). Academic treatment optimization studies in oncology and internal medicine: a risk- and burden-adapted regulatory framework for the European Union. The Lancet Regional Health – Europe, 71, Article 101888. https://doi.org/10.1016/j.lanepe.2026.101888

Image Credits: AI Generated

DOI: 10.1016/j.lanepe.2026.101888

Keywords: clinical trials, EU regulation, oncology, pediatric oncology, treatment optimization, investigator-initiated trials, Clinical Trials Regulation, risk-proportionate oversight, medical societies, health policy, internal medicine, European Biotech Act