Biologic drugs are highly complex molecules produced by living cells through a multistep manufacturing process. The key characteristics of these molecules, known as critical quality attributes (CQAs), can vary based on post-translational modifications that occur in the cellular environment or during the manufacturing process. The extent of the variation in each of the CQAs must be characterized for the originator molecule and systematically matched as closely as possible by the biosimilar developer to ensure bio-similarity. The close matching of the originator fingerprint is the foundation of the biosimilarity exercise, as the analytical tools designed to measure differences at the molecular level are far more sensitive and specific than tools available to physicians during clinical trials. Biosimilar development, therefore, has a greater focus on preclinical attributes compared with the development of an original biological agent. As changes in CQAs can occur at different stages of the manufacturing process, even small modifications to the process can alter biosimilar attributes beyond the point of similarity and impact clinical effectiveness and safety. The manufacturer’s ability to provide consistent production and quality control will greatly influence the acceptance of biosimilars. To this end, preventing drift from the required specifications over time and avoiding the various implications brought by product shortage will enhance biosimilar integration into daily practice. As most prescribers are not familiar with this new drug development paradigm, educational programmes will be needed so that prescribers see biosimilars as fully equivalent, efficacious and safe medicines when compared with originator products.

Biosimilar medicines have shown similarity with the originator biologic and offer a similar clinical outcome generally at a lower cost. This paper identifies benefits of off-patent biologics and biosimilars, and illustrates these benefits with empirical data from Europe. We provide a narrative review of published literature on values and benefits of biosimilars in Europe. The results describe cost savings as the key driver stemming from the lower price of biosimilars, than that of originator products, and from price competition between biosimilar(s), originator, and next-generation products. Cost savings may then translate into a number of other associated benefits. The lower price of biosimilars and similar effectiveness to the originator biologics improve cost effectiveness, implying that reimbursement can be granted or extended to other patient groups, or that the biologic therapy can be moved to an earlier line of treatment. Cost savings from biosimilars can be used to increase patient access to therapy or to increase the number of healthcare professionals. Finally, competition between off-patent biologics and biosimilars may stimulate an innovation in the formulation and development of next-generation biologics. Our paper illustrates that the benefit of off-patent biologics and biosimilars is not restricted to cost savings, but that these medicines may contribute to an expansion of medical treatment options for patients, hence concomitantly contributing to the long-term sustainability of the healthcare system. This review provides a broader view for clinical and economic decision makers and healthcare professionals on the added benefits of off-patent biologics and their use in clinical practice.

Purpose: Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma. Patients and Methods: Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding. Results: Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. Four patients demonstrated tumor response on MRI, one with complete regression and still alive after 8 years. Most serious adverse events were attributed to increased intracranial pressure caused by either an inflammatory reaction responding to steroid treatment or viral meningitis being transient and self-limiting. Often viral DNA concentrations in CSF increased over time, peaking after 2 to 4 weeks and remaining up to 3 months. Concomitantly Th1- and Th2-associated cytokine levels and numbers of CD3+ T and natural killer cells increased. Posttreatment tumor specimens revealed increased numbers of macrophages and CD4+ and CD8+ T cells. No evidence of viral shedding in excreta was observed. Conclusions: CED of Delta24-RGD not only in the tumor but also in surrounding brain is safe, induces a local inflammatory reaction, and shows promising clinical responses.

The nocebo effect is defined as the incitement or the worsening of symptoms induced by any negative attitude from non-pharmacological therapeutic intervention, sham, or active therapies. When a patient anticipates a negative effect associated with an intervention, medication or change in medication, they may then experience either an increase in this effect or experience it de novo. Although less is known about the nocebo effect compared with the placebo effect, widespread interest in the nocebo effect observed with statin therapy and a literature review highlighting the nocebo effect across at least ten different disease areas strongly suggests this is a common phenomenon. This effect has also recently been shown to play a role when introducing a medication or changing an established medication, for example, when switching patients from a reference biologic to a biosimilar. Given the important role biosimilars play in providing cost-effective alternatives to reference biologics, increasing physician treatment options and patient access to effective biologic treatment, it is important that we understand this phenomenon and aim to reduce this effect when possible. In this paper, we propose three key strategies to help mitigate the nocebo effect in clinical practice when switching patients from reference biologic to biosimilar: positive framing, increasing patient and healthcare professionals’ understanding of biosimilars and utilising a managed switching programme.

Background Despite the benefits offered by biosimilars in terms of cost savings and improved patient access to biological therapies, and an established regulatory pathway in Europe, biosimilar adoption is challenged by a lack of knowledge and understanding among stakeholders such as healthcare professionals and patients about biosimilars, impacting their trust and willingness to use them. In addition, stakeholders are faced with questions about clinical implementation aspects such as switching. Objective This study aims to provide recommendations on how to improve biosimilar understanding and adoption among stakeholders based on insights of healthcare professionals (physicians, hospital pharmacists, nurses), patient(s) (representatives) and regulators across Europe. Method The study consists of a structured literature review gathering original research data on stakeholder knowledge about biosimilars, followed by semi-structured interviews across five stakeholder groups including physicians, hospital pharmacists, nurses, patient(s) (representatives) and regulators across Europe. Results Although improvement in knowledge was observed over time, generally low to moderate levels of awareness, knowledge and trust towards biosimilars among healthcare professionals and patients are identified in literature (N studies = 106). Based on the provided insights from interviews with European experts (N = 44), a number of challenges regarding biosimilar stakeholder understanding are identified, including a lack of practical information about biosimilars and their use, a lack of understanding about biosimilar concepts and a lack of knowledge about biologicals in general. Misinformation by originator industry is also believed to have impacted stakeholder trust. In terms of possible solutions and actions to improve stakeholder understanding, broad support exists to (1) organize initiatives focussed on explaining the rationale behind biosimilar concepts and the approval pathway, (2) invest in education about biologicals in general, (3) develop clear and one-voice regulatory guidance about biosimilar interchangeability and switching across Europe, (4) disseminate real-world clinical biosimilar (switch) data, (5) share biosimilar experiences by key opinion leaders and among peers, (6) provide practical biosimilar product information, (7) provide guidance about biosimilar use, (8) actively counterbalance misinformation and organize information initiatives by neutral entities, (9) organize multi-stakeholder informational and educational efforts, aligning information between involved stakeholder groups and (10) design initiatives in a way that ensures active information uptake. Furthermore, interviewees argue that governments should be proactive in these regards. Conclusions This study argues in favour of a structural, multi-stakeholder framework at both European and national level to improve stakeholder biosimilar understanding and acceptance. It proposes a number of actionable recommendations that can inform policy making and guide stakeholders, which can contribute to realizing healthcare system benefits offered by biosimilar competition.