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

The entry of adalimumab biosimilars in Europe : an overview of price evolution and country responses

Background: From October 2018, adalimumab biosimilars could enter the European market. However, some countries, such as the Netherlands, report high discounts for the originator product that influence biosimilar entry. Consequently, we researched European (list) prices and reimbursement status of originator adalimumab, before and after the entry of biosimilars, and discuss relevant policy measures. Methods: Survey distributed via email to national experts consisting of three parts: i) general financing/co-payment of medicines, ii) reimbursement status and prices of originator adalimumab and availability of biosimilars, and iii) policy measures related to the use of adalimumab. Results: In the 27 surveyed countries, originator adalimumab is reimbursed (fully or only partial, and sometimes with restrictions in use), except for Kosovo, where it is not marketed. Following adalimumab biosimilars, a few countries have made changes to the reimbursement status/level or setting where adalimumab is available. Overall, a decrease in list prices of originator adalimumab was seen after loss of exclusivity rights. Some countries (Bulgaria, Germany, Greece, Italy, Latvia, the Netherlands and Romania) reported that list prices have not changed up to May 2019, although confidential discounts may exist. Adalimumab biosimilars were available in 23 of the 27 surveyed countries. Countries adopted various approaches to leverage competition from the use of (biosimilar) adalimumab. In some countries, a strategy was implemented even before patent expiry (Scotland), while others did not report specific measures. Conclusion: This study documented how European countries responded differently to patent expiry of originator adalimumab and biosimilar market entry, with implications for pricing and reimbursement

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

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

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

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

学習塾の原点を見つめ直す : 学習塾の存在意義とは

Background: Biosimilars are medicinal products that are similar to a biopharmaceutical that has already been authorised. As biopharmaceuticals are expected to dominate the best-selling pharmaceuticals worldwide by 2016, the emergence of biosimilars imposes an important challenge for governments. At this moment, the uptake of biosimilars in Belgium is limited, with market shares close to 0 %. Objective: This study aimed to identify the barriers that impede the uptake of biosimilars in Belgium. Methods: Semi-structured interviews were conducted to investigate in depth the barriers to the uptake of biosimilars in Belgium. Respondents were selected through selective sampling so that all different stakeholders were represented (authorities, physicians, pharmacists, patients, academics and industry). Respondents were contacted by e-mail and letter with a request for participation. A thematic framework was used to analyze the data. Results: Three main barriers to the uptake of biosimilars in the Belgian market were identified: a lack of confidence towards biosimilars by some stakeholders; uncertaint