The process defines the product: what really matters in biosimilar design and production?

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

Biosimilars in Belgium: a proposal for a more competitive market

More than ten years after the first biosimilars were authorized for use in the European Union, Belgium still experiences limited competition from biosimilars, as exemplified by low market shares. Achieving high biosimilar market shares is not necessarily a goal in itself, as cost savings are also realized by mandatory price reductions on originator medicines in Belgium. However, we believe that biosimilars play a role in ensuring the long-term sustainability of the off-patent biologicals market. It is therefore crucial to list what has been done and what is needed to support the Belgian government in establishing a policy framework for a competitive off-patent biologicals market. We provide a comprehensive overview of the Belgian biosimilar market, including existing hurdles for biosimilar use in Belgium. Based on these hurdles and supplemented with learnings from other European countries, we propose practical recommendations that can be implemented to overcome them. Several Belgian stakeholders had the opportunity to comment on these recommendations. Specifically, we suggest to evolve towards a long-term consistent, integrated policy framework via i) the creation of a proactive and transparent climate supporting a level playing field for both biosimilar and reference product, including public dissemination of how savings at the level of the Belgian healthcare system are used, ii) investment in educational activities, including raising awareness of societal responsibility, iii) enforcement of the practical implementation of public procurement law, and iv) the development of incentives for physicians, who are key stakeholders in the Belgian off-patent biologicals market

A health economic guide to market access of biosimilars

Introduction: Little is known about market access to biosimilars from a health economic perspective, except for studies that compute the budget impact of biosimilar use. Areas covered: This comprehensive health economic guide to the market access of biosimilars focuses on the role of biosimilars in pharmaceutical innovation and competition, the objective of biopharmaceutical policy, the budget impact of biosimilars, and the cost-effectiveness of biologic therapy in the presence of biosimilars. Expert opinion: We argue that the objective of biopharmaceutical policy in a health system should be to create a competitive and sustainable market for off-patent reference biologics, biosimilars, and next-generation biologics that makes biologic therapy available to patients at the lowest cost. Market access of biosimilars can contribute to this objective as a result of the lower price of biosimilars and price competition with alternative therapies. The resulting improvement in the cost-effectiveness of biologic therapy needs to be accounted for by revisiting reimbursement decisions and conditions. When examining the cost-effectiveness of biologic therapy following patent expiry, stakeholders need to consider residual uncertainties at the time of biosimilar marketing authorization, the nocebo effect, market entry of a second-generation reference biologic with a different administration form than the biosimilar, and value-added services

An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry?

As patents on many high-selling biological medicines are expiring, non-innovator versions, such as biosimilars, may enter this multi-billion dollar market. This study aims to map patents and patent applications for innovator as well as biosimilar monoclonal antibodies in Europe, and investigates legal challenges associated with patenting the innovator product and alleged infringing activities, focusing on consequences for biosimilar developers. Via an exploratory literature review in PubMed and a database analysis in Darts-ip, Derwent Innovation, and Espacenet, an overview of basic patents and exclusivity rights for some of the best-selling biologicals is given, supplemented with a detailed analysis of patents taken during the medicine’s life cycle via three specific case studies (trastuzumab, bevacizumab, cetuximab). Case law was used to determine which patents were viewed by biosimilar developers as blocking market entry. For the selected monoclonal antibodies, the key protection instruments appeared to be the basic patent and the additional protection provided by a supplementary protection certificate. We observed that additional patents filed after the basic patent are hard to obtain and often insufficient in blocking market entry of biosimilars, but can in some cases be a substantial hurdle for biosimilar developers to overcome in patent litigation cases or to invent around, creating uncertainty on the launch date of a biosimilar on the market. These hurdles, however, seem to be surmountable, given that many cases were won by biosimilar developers. Also, biosimilars can be protected by filing new patents and these mainly pertain to new formulations

Biosimilar Pegfilgrastim: Improving Access and Optimising Practice to Supportive Care that Enables Cure

Febrile neutropenia (FN) is a serious complication of chemotherapy, which can cause significant morbidity and mortality, result in dose delays and reductions and, ultimately, reduce cancer survival. Over the past decade, the availability of biosimilar filgrastim (short-acting granulocyte colony-stimulating factor [G-CSF]) has transformed patient access, with clear evidence of clinical benefit at preventing FN at reduced costs. In 2019, seven biosimilar pegfilgrastims (long-acting G-CSFs) were licensed, creating optimal market conditions and choice for prescribers. FN affects up to 117 per 1000 cancer patients, with mortality rates in the range of 2–21%. By reducing FN incidence and improving chemotherapy relative dose intensity (RDI), G-CSF has been associated with a 3.2% absolute survival benefit. Guidelines recommend primary prophylaxis and that filgrastim be administered for 10–14 days, while pegfilgrastim is administered once per cycle. When taken according to the guidelines, pegfilgrastim and filgrastim are equally effective. However, in routine clinical practice, filgrastim is often under-dosed (< 7 days) and has been shown to be inferior to pegfilgrastim at reducing FN incidence, hospitalisations and maintaining RDI. Once-per-cycle administration with pegfilgrastim might also aid patient adherence. The introduction of biosimilar pegfilgrastim should instigate a rethink of neutropenia management. Biosimilar pegfilgrastim

Identifying Key Benefits in European Off-Patent Biologics and Biosimilar Markets: It is Not Only About Price!

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 pa

European Stakeholder Learnings Regarding Biosimilars: Part II—Improving Biosimilar Use in Clinical Practice

Background Despite the benefts biosimilars ofer in terms of cost savings and patient access, healthcare professionals and patients have been reluctant to use them. Next to insufcient understanding of and trust in biosimilars, healthcare professionals and patients have questions about switching and the nocebo efect when using biosimilars in clinical practice. In addition, clear motivation to use biosimilars may be lacking among these stakeholders. Objective This study aims to provide recommendations on how to improve biosimilar use on both a clinical and a practical level based on insights from healthcare professionals (physicians, hospital pharmacists, nurses), patients (or their representatives), and regulators across Europe. Methods We conducted 44 semi-structured interviews with experts from fve stakeholder groups across Europe: physicians, hospital pharmacists, nurses, regulators, and patients/representatives. Interviews were transcribed ad verbatim and transcripts analysed according to the thematic framework method. Results Based on the insights and considerations of the experts interviewed, we identifed a number of recommendations to improve the use of biosimilars in clinical practice. Regarding switch implementation, the experts voiced support for the following actions: (1) disseminate evidence from and experience with (multiple) switching; (2) provide clear, one-voice regulatory guidance about the interchangeability of biosimilars and their reference product; (3) apply a multi-stakeholder implementation and communication protocol to guide switching in clinical practice; (4) apply a pragmatic approach when taking switch decisions; and (5) avoid mandated switching, allowing stakeholder communication and alignment. When discussing approaches to increas

European Stakeholder Learnings Regarding Biosimilars: Part I—Improving Biosimilar Understanding and Adoption

Background Despite the benefts ofered 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 fve 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 identifed 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 identifed, 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

Changes in antibiotic use in Dutch hospitals over a six-year period: 1997 to 2002

OBJECTIVE: To analyse trends in antibiotic use in Dutch hospitals over the period 1997 to 2002. METHODS: Data on the use of antibiotics and hospital resource indicators were obtained by distributing a questionnaire to all Dutch hospital pharmacies. Antibiotic use was expressed as the number of defined daily doses (DDD) per 100 patient-days and as DDD per 100 admissions. RESULTS: Between 1997 and 2002, the mean length of stay decreased by 18%. The mean number of admissions remained almost constant. Total antibiotic use significantly increased by 24%, from 47.2 in 1997 to 58.5 DDD per 100 patient-days in 2002 (p<0.01), whereas expressed as DDD per admissions it remained constant. Antibiotic use varied greatly between the hospitals. Moreover, the mean number of DDD per hospital of amoxicillin with clavulanic acid, clarithromycin, cefazolin, clindamycin and ciprofloxacin increased by 16, 38, 39, 50 and 52%, respectively. Total antibiotic use was higher in university hospitals than in general hospitals. CONCLUSIONS: Between 1997 and 2002, patients hospitalised in the Netherlands did not receive more antibiotics but, since they remained in the hospital for fewer days, the number of DDD per 100 patient-days increased. For macrolides, lincosamides and fluoroquinolones increases in both DDD per 100 patient-days and in DDD per 100 admissions were observed. It is arguable whether these trends result in an increase in selection pressure towards resistance in the hospitals. Continuous surveillance of antibiotic use and resistance is warranted to maintain efficacy and safety of antibiotic treatment