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Aims: In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn's disease (CD) on ustekinumab achieved endoscopic response and 10.9% of patients achieved endoscopic remission at week (w)44. We aimed to evaluate the impact of alternative ustekinumab dosage regimens on endoscopic outcomes based on population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods: Real-world data were obtained from 83 patients with moderate-to-severe CD (95% biological-refractory) enrolled in a prospective cohort study receiving intravenous ustekinumab (similar to 6 mg/kg) followed by every eight-week (q8w) subcutaneous maintenance therapy (90 mg). Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fecal calprotectin (fCal), and a logistic regression outcome model linking fCal to endoscopic outcomes. Results: Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1800 mu g/g to 694 mu g/g (EC50). The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1800 mu g/g to 214 mu g/g (EC50). Simulation-based comparison of q8w and q4w maintenance dosing regimens predicted 16.7% and 22.2% endoscopic response rates, respectively. Endoscopic remission rates were estimated to be 4.2% on q8w dosing and 6.7% on q4w dosing. Conclusions: The developed models can guide clinical trial design and support model-informed dose optimization (stratified or individualized dosing) to improve endoscopic outcomes.

Background: Beyond evaluation and approval, European and national regulators have a key role in providing reliable information on biosimilars and the science underpinning their development, approval, and use. Objectives: This study aims to (i) review biosimilar information and guidance provided by EMA and national medicines agencies and (ii) explore stakeholder perspectives on the role of regulators in enabling acceptance and use of biosimilars. Methods: This study consists of (i) a comparative review of regulatory information and position statements across medicine agencies (n = 32) and (ii) qualitative interviews with stakeholders in Europe (n = 14). Results: The comparative analysis showed that regulatory information and guidance about biosimilars offered by national medicines agencies in Europe varies, and is limited or absent in multiple instances. Approximately 40% (13/31) of the national medicines agencies' websites did not offer any information regarding biosimilars, and for about half (15/31) no educational materials were provided. Only less than half of national medicines agencies provided guidance on biosimilar interchangeability and switching (8/31 and 12/31, respectively). Among the national medicines agencies that did offer guidance, the extent (e.g., elaborate position vs. brief statement) and content (e.g., full endorsement vs. more cautious) of the guidance differed substantially. Countries that have a strong involvement in EU level biosimilar regulatory activities generally had more elaborate information nationally. Interviewees underwrote the need for (national) regulators to intensify biosimilar stakeholder guidance, especially in terms of providing clear positions regarding biosimilar interchangeability and switching, which in turn can be disseminated by the relevant professional societies more locally. Conclusion: This study revealed that, despite strong EU-level regulatory biosimilar guidance, guidance about biosimilars, and their use diffe

Background: By improving the affordability and accessibility of biologicals, biosimilar competition provides important benefits to healthcare systems and patients. In Belgium, biosimilar uptake and competition is limited compared to other European markets. Whereas other countries have initiated structured biosimilar introduction or switching plans, no such framework or guiding principles are yet available in Belgium. Objective: This study aims to develop recommendations that can inform policy action in Belgium on biosimilar use, especially in the context of switch decision-making, and this by drawing from the perspectives of healthcare professionals involved in procuring, prescribing, switching and dispensing biologicals including biosimilars. Methods: This study made use of the consensus-building Nominal Group Technique, consisting of a three-step process 1) individual grading, 2) three structured Focus Group Discussions, 3) final individual grading involving an expert group of Belgian healthcare professionals (physician specialists and hospital pharmacists). Results: Participants (n = 13) voiced challenges with the use of biosimilars and switching in practice, and a lack of incentives to use them. Six concrete areas for policy development to support stakeholders with biosimilar use and switch decision-making were identified: 1) address stakeholder hesitations regarding (multiple) switching, 2) provide meaningful incentives, 3) guide healthcare professionals with product decision-making, 4), align practical product modalities when possible, 5) involve healthcare professionals in policy making, and 6) provide practical switch support and patient information material, particularly in the ambulatory care setting. For each area, specific consensus-based recommendations were developed. Furthermore, a set of switch management and patient communication principles was derived, including amongst others, generating buy-in from involved stakeholders prior to switching and