Judith Ekkina Bosmans

AI-enabled digital medicine platforms in Europe are developed within overlapping rules for personal data, medical devices, AI, clinical research, health data access, and health technology assessment. This viewpoint represents the authors’ experience and interpretation from the preimplementation phase of INTERCEPT, an Innovative Health Initiative consortium that plans to validate biomarkers and develop a blood-based risk score for early Crohn disease interception. It does not report original empirical research, a systematic regulatory review, a deployed platform, or a validated AI model. Our aim is to explain how compliance-by-design can be translated into an auditable governance architecture and to identify what still requires scientific evaluation. We advance 3 messages. First, governance must begin with intended purpose and boundary mapping: a digital platform may contain research, operational, and medical device software functions, and conformity of one module cannot be inferred for the platform as a whole. Second, overlapping obligations can be operationalized through 5 linked controls: modular responsibility and change control, federated data governance, traceable AI life cycle management, consent and participant rights orchestration, and a common cross-border governance core with local adaptations. Third, compliance is not a surrogate for model validity, clinical benefit, trust, scalability, or market access. Before clinical deployment, planned AI components require prespecified labels and cohorts, leakage prevention, missing data and imbalance strategies, calibration, subgroup assessment, external validation, human factors evaluation, and postdeployment algorithmovigilance. A hypothetical biomarker risk score update illustrates how the 5 controls interact. INTERCEPT is informative because it combines cross-border biomarker research, planned predictive analytics, and heterogeneous institutional settings while key design decisions remain modifiable. Its contribution is nevertheless conceptual: the proposed framework is a testable governance hypothesis, not evidence of implementation success. Prospective studies should compare it with alternative governance models and assess safety, workload, participant experience, evidence generation, and regulatory performance.

Background: Cognitive behavioral therapy (CBT) is an effective and widely used treatment for major depressive disorder (MDD). However, access is limited by long waiting lists and a shortage of trained therapists. Evidence-based guided and self-guided digital interventions can address these challenges, but their large-scale adoption in routine primary and specialized mental health care has been slow. Blended CBT (bCBT), combining face-to-face therapy with structured, guided digital treatment modules, may increase treatment capacity while maintaining the benefits of therapist support. Objective: The European Comparative Effectiveness Research on Internet-based Depression Treatment study, conducted across 9 European countries, is the first large-scale comparative bCBT study for MDD. The hypothesis was that bCBT is clinically noninferior and cost-effective when compared with treatment as usual (TAU), which mainly consisted of face-to-face CBT. Methods: A multisite randomized controlled trial was conducted with a noninferiority margin of d =0.20. Main inclusion criteria were age ≥18 years, a diagnosis of MDD based on the Mini International Neuropsychiatric Interview, and a baseline Patient Health Questionnaire-9 (PHQ-9) score of ≥5. The primary outcome was the PHQ-9, with secondary outcomes including MDD remission at 12 months, therapeutic alliance, and costs. Intention-to-treat analyses were performed, and linear mixed modeling was used to assess intervention effects. Cost-effectiveness analyses were conducted from a health care perspective. Results: A total of 835 patients were included in the study. bCBT was shown to be noninferior to TAU on the primary PHQ-9 outcome during treatment (3 months after the baseline assessment, d =−0.26, 95% CI −0.43 to −0.09), at 6 months (posttreatment, d =−0.21, 95% CI −0.39 to−0.04), and at 12-month follow-up ( d =−0.01, 95% CI −0.19 to 0.17). Furthermore, the bCBT group had a significantly lower likelihood of experiencing an MDD episode at 12 months (odds ratio 0.67, 95% CI 0.45‐0.99). Subgroup analyses indicated that participants with and with no antidepressant use at baseline in both groups benefited equally from their treatment. Deterioration rates (Reliable Change Index) were below 5% in both groups. bCBT appeared acceptable for patients and therapists, with a strong working alliance in both groups. From a health care perspective, bCBT was not cost-effective at 12 months' assessment, as its total costs were not significantly lower than TAU. However, the probability that bCBT is cost-effective is high (0.95) at a willingness to pay (WTP) of €3800 per improvement in the PHQ-9 score, and 0.76 at a WTP of €10,000 per MDD case prevented (average 2017 exchange rate was €1=US $1.13). Conclusions: bCBT offers an effective and safe digitally supported alternative to face-to-face TAU for patients with MDD and their therapists in routine clinical care. From a health care perspective, its cost-effectiveness depends on policymakers’ WTP for the additional clinical benefits achieved.

Background: Obsessive-compulsive disorder (OCD) is a disabling mental disorder, characterized by obsessions, compulsions, and substantial morbidity. Approximately 50% of adults with OCD fail to achieve satisfactory outcomes from first-line treatments, such as exposure therapy with response prevention (ERP), with or without medication. This leads to chronic social, educational, and occupational impairment. While invasive procedures such as deep brain stimulation are available for severe, treatment-refractory cases, a need remains for less invasive alternatives. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive intervention, shows promise in reducing OCD symptoms. Unlike in depression, rTMS is not yet reimbursed for OCD in the Dutch healthcare system. Objective: This study examines the efficacy and cost-effectiveness of low-frequency (1Hz) rTMS targeting the presupplementary motor area (pre-SMA) compared to sham rTMS as an adjuvant treatment to ERP in adults with OCD with inadequate response to first-line treatment. Methods: A total of 250 adults with OCD will be enrolled in this multicenter randomized controlled trial. Participants will be randomly assigned to ERP combined with either active or sham 1Hz rTMS over the pre-SMA. Treatment is administered 4 times weekly for at least 5 weeks (20 rTMS-ERP sessions), with optional extension of 1 to 2 weeks, up to 28 rTMS-ERP sessions. Clinical assessments occur at baseline, weekly during treatment, posttreatment, and at 3, 6, and 12 months follow-up. Participants undergo pre- and posttreatment (functional) (MRI) scans, including a symptom provocation task. Blood sampling takes place pre- and posttreatment and at 3-month follow-up. The primary outcome is OCD severity at posttreatment, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Secondary outcomes include functional improvement, quality of life, and societal costs. Pretreatment symptom profiles, genotype, and brain network topology will be analyzed as predictors of response and relapse risk. Pre-to-post treatment change in blood-based and magnetic resonance (MR)-based neuroplasticity markers will help explore differential mechanisms between ERP alone and combined rTMS-ERP. We expect that the verum rTMS protocol will be cost-effective compared to sham-rTMS. Results: Recruitment started in April 2022, and as of February 2026, 201 participants have been enrolled. Posttreatment assessments are projected to be completed in December 2026, with final one-year follow-up evaluations anticipated by the end of 2027. Conclusions: To our knowledge, this study is the first adequately powered randomized controlled trial examining efficacy, cost-effectiveness, and mechanism of action of rTMS for OCD as adjuvant therapy to ERP. In case of efficacy and/or cost-effectiveness, it will pave the way for rTMS as insured health care for adults with OCD in the Netherlands, and possibly other European countries. Furthermore, this trial will provide insight into the mechanisms of treatment response to intensive ERP, with and without adjunctive rTMS, as well as potential side effects, individual variability, and long-term outcomes in adults with OCD.

Introduction: Osteoarthritis (OA) is a chronic joint disease, often leading to pain, joint stiffness and impaired function. The first metatarsophalangeal (MTP-1) joint is the most frequently affected joint in foot OA. Footwear interventions might have potential to reduce pain for people with MTP-1 joint OA. The aim of this study is to determine the effectiveness and cost-effectiveness of orthopaedic modifications to off-the-shelf footwear in addition to usual care, compared to usual care alone, for people with MTP-1 joint OA. Methods and analyses: We perform a pragmatic, non-blinded, two-armed, parallel-group, randomised controlled trial (RCT). A total of 136 people with MTP-1 joint OA and presence of foot pain are recruited. Participants are randomised to orthopaedic modifications to off-the-shelf footwear in addition to usual care or to usual care alone. The footwear modifications comprise a combination of sole-stiffening, rocker sole adjustments and custom-made insoles. During a 12-month follow-up period, participants receive monthly questionnaires. Primary outcomes include walking pain at 6-month follow-up and quality-adjusted life years and societal costs at 12-month follow-up. Secondary outcomes include walking pain at 12-month follow-up and foot health, physical activity level, patient acceptability and self-reported recovery at 6- and 12-month follow-up. Intention-to-treat and per-protocol analyses will be performed using (generalised) linear mixed models. Ethics and dissemination: The study is approved by the local Medical Ethics Committee of the Erasmus MC University Medical Center Rotterdam, The Netherlands (MEC-2024-0615). Prior to study participation, participants provide informed consent. Results will be disseminated amongst researchers through peer-reviewed scientific articles and presentations at conferences; and amongst people with MTP-1 joint OA and healthcare professionals through layman articles in newsletters, on websites and on social media. Discussion: This is the first RCT to investigate the effectiveness and cost-effectiveness of orthopaedic modifications to off-the-shelf footwear in addition to usual care, compared to usual care alone for people with MTP-1 joint OA. Study findings will support healthcare professionals in making substantiated decisions in the treatment of people with MTP-1 joint OA. Trial registration number: Overview of Medical Research in the Netherlands (OMON): NL87646.078.24

BACKGROUND Obsessive-compulsive disorder (OCD) is a disabling mental disorder, characterized by obsessions, compulsions and substantial morbidity. Approximately 50% of adults with OCD fail to achieve satisfactory outcomes from first-line treatments such as exposure therapy with response prevention (ERP) with or without medication. This leads to chronic social, educational, and occupational impairment. While invasive procedures such as deep brain stimulation are available for severe, treatment-refractory cases, a need remains for less invasive alternatives. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive intervention, shows promise in reducing OCD symptoms. Unlike in depression, rTMS is not yet reimbursed for OCD in the Dutch healthcare system. OBJECTIVE This study examines the efficacy and cost-effectiveness of low-frequency (1Hz) rTMS targeting the pre-supplementary motor area (pre-SMA) compared to sham rTMS as an adjuvant treatment to ERP in adults with OCD with inadequate response to first-line treatment. METHODS 250 adults with OCD will be enrolled in this multicenter randomized controlled trial. Participants will be randomly assigned to ERP combined with either active or sham 1Hz rTMS over the pre-SMA. Treatment is administered four times weekly for at least five weeks (20 rTMS-ERP sessions), with optional extension of one to two weeks, up to 28 rTMS-ERP sessions. Clinical assessments occur at baseline, weekly during treatment, post-treatment, and at 3, 6, and 12 months follow-up. Participants undergo pre- and post-treatment (functional) MRI scans, including a symptom provocation task. Blood sampling takes place pre- and post-treatment and at 3 months follow-up. The primary outcome is OCD severity at post-treatment, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Secondary outcomes include functional improvement, quality of life and societal costs. Pre-treatment symptom profiles, genotype, and brain network topology will be analyzed as predictors of response and relapse risk. Pre-to-post treatment change in blood-based and MR-based neuroplasticity markers will help explore differential mechanisms between ERP alone and combined rTMS-ERP. We expect that the verum rTMS protocol will be (cost-)effective compared to sham-rTMS. RESULTS Recruitment started in April 2022, and as of February 2026, 201 participants have been enrolled. Post-treatment assessments are projected to be completed in December 2026 with final one-year follow-up evaluations anticipated by the end of 2027. CONCLUSIONS To our knowledge, this study is the first adequately-powered randomized controlled trial examining efficacy, cost-effectiveness and mechanism of action of rTMS for OCD as adjuvant therapy to ERP. In case of efficacy and/or cost-effectiveness, it will pave the way for rTMS as insured health care for adults with OCD in the Netherlands, and possibly other European countries. Furthermore, this trial will provide insight into the mechanisms of treatment response to intensive ERP, with and without adjunctive rTMS, as well as potential side effects, individual variability, and long-term outcomes in adults with OCD. CLINICALTRIAL This trial is registered at clinicaltrials.gov with code: NCT05331937, last updated on January 15th 2026.

Background: Falls among older adults are a growing public health issue, and are associated with injuries and increased societal costs. Therefore, implementation of effective fall prevention interventions is important. Given limited healthcare resources, evaluating the cost-effectiveness of these interventions is essential. Therefore, we aimed to evaluate the cost-effectiveness of the In Balance fall prevention intervention for community-dwelling older adults with an increased risk of falls compared to general physical activity recommendations (control) from a societal perspective. Methods: An economic evaluation was conducted alongside a twelve month, single-blind, multicenter randomized controlled trial. Participants were 264 non- and pre-frail community-dwelling adults aged 65 years or older with an increased fall risk. We assessed costs from a societal perspective and effects included the number of falls, fall-related injuries, and Quality-Adjusted Life Years (QALYs) based on the EuroQol Five-level questionnaire (EQ-5D-5L) and the Adult Social Care Outcomes Toolkit (ASCOT). Missing data were handled using Multiple Imputation by Chained Equations (MICE). Incremental costs and effects were estimated using Seemingly Unrelated Regressions and used to estimate Incremental cost-effectiveness ratios (ICERs). Results: On average, In Balance was less expensive and more effective than control, but differences were not statistically significant. ICERs indicated dominance of the intervention for prevented falls (€-14,329 per prevented fall), prevented fall-related injuries (€-14,569 per prevented injury), and QALYs based on both the EQ-5D-5L (€-168,265 per QALY gained) and ASCOT (€-135,797 per QALY gained). The probability of cost-effectiveness of In Balance compared to control was 98% at a willingness to pay (WTP) of €0 per unit of effect gained. Conclusions: Based on this study, we conclude that In Balance may be considered cost-effective compared to control. Future research should explore whether In Balance as part of a comprehensive fall prevention strategy is cost-effective. Trial registration: Research with human participants: NL9248 (registered February 13 2021, URL: https://www.onderzoekmetmensen.nl/nl/trial/26195 )

To assess the effectiveness of allied healthcare versus no allied healthcare. Data from the ParaCOV cohort (allied healthcare, n = 1,451) and the LongCOVID cohort (no allied healthcare/control, n = 1427) were analyzed. Average treatment effects (ATEs) between groups were estimated using Targeted Maximum Likelihood Estimation adjusted for age, sex, body mass index, smoking status, comorbidities, and effect outcomes' baseline values. A ≥ 10% between-group difference in improvement from baseline (BTGD) was considered clinically relevant for participation, fatigue, and physical functioning, and ≥0.062 for health-related quality of life. Patients receiving allied healthcare were older (49.2 vs. 41.2 years), less often female (63.3% vs. 70.1%), had higher BMI (28.2 vs. 26.1), smoked less frequently (5.0% vs. 9.0%), had more comorbidities (49.2% vs. 41.9%), and lower baseline anxiety and depression scores compared to those not receiving allied healthcare. For participation, ATEs after 6 and 12 months were respectively -2.62 (95%CI: -4.39; -0.86) and -1.68 (95%CI: -4.81;1.45), with BTGDs of 4.7% and 1.8% favoring the control. For fatigue, ATEs were 1.72 (95%CI: -0.14; 3.58) and 0.97 (95%CI: -1.48; 3.41), with BTGDs of 6.5% and 3.7% favoring the control. For physical functioning, ATEs were 5.75 (95% CI: 4.42; 7.09) and 6.36 (95%CI: 4.84; 7.88), with BTGDs of 1.4% and 2.2% favoring allied healthcare. For health-related quality of life, ATEs were 0.017 (95%CI: -0.008; 0.0044) and 0.033 (95%CI: 0.011; 0.054). Patients with persistent complaints after a COVID-19 infection showed significantly lower participation after 6 months, higher health-related quality of life after 12 months, and better physical functioning after 6 and 12 months of allied healthcare, however, BTGDs were not clinically relevant. Study limitations warrant cautious results interpretation.

In recent years, theoretical results and simulation evidence have shown Bayesian additive regression trees to be a highly-effective method for nonparametric regression. Motivated by cost-effectiveness analyses in health economics, where interest lies in jointly modelling the costs of healthcare treatments and the associated health-related quality of life experienced by a patient, we propose a multivariate extension of BART which is applicable in regression analyses with several dependent outcome variables. Our framework allows for continuous or binary outcomes and overcomes some key limitations of existing multivariate BART models by allowing each individual response to be associated with different ensembles of trees, while still handling dependencies between the outcomes. In the case of continuous outcomes, our model is essentially a nonparametric version of seemingly unrelated regression. Likewise, our proposal for binary outcomes is a nonparametric generalisation of the multivariate probit model. We give suggestions for easily interpretable prior distributions, which allow specification of both informative and uninformative priors. We provide detailed discussions of MCMC sampling methods to conduct posterior inference. Our methods are implemented in the R package subart. We showcase their performance through extensive simulation experiments and an application to an empirical case study from health economics. By also accommodating propensity scores in a manner befitting a causal analysis, we find substantial evidence for a novel trauma care intervention’s cost-effectiveness.