A multifaceted view on market access of biosimilars

This PhD project aims to study multiple aspects of market access of biosimilars in Europe, with the ultimate goal to formulate recommendations supporting a long-term sustainable biologicals market in the presence of biosimilars. Biosimilars contain an active substance that is proven to be similar, in terms of quality, safety and efficacy, to that of an authorized biological product (reference product) after extensive comparability testing. Following expiry of patent protection and other exclusivity rights on the reference product, these rights may not hinder anymore the market entry of the biosimilar. Once on the market, biosimilars will induce competition leading to cost savings and/or increased patient access to treatment. However, variation in uptake of biosimilars between countries and between active substances for which biosimilars are available, might indicate that countries are not able to fully capture the benefits of competition from biosimilars and urges to study market access of biosimilars in a multifaceted way. Part 1 of this PhD project, provides a general introduction to the topic of market access of biosimilars and explains the rationale and specific objectives of this PhD project (Chapter 1).In Part 2, barriers to the market access of biosimilars and general recommendations to overcome these barriers are described. In Chapter 2, six barriers were reported, as identified in 2015: the manufacturing process, the regulatory process, intellectual property rights, lack of incentive, the impossibility of substitution, and the innovator's reach. For each of these barriers, recommendations were developed to reduce these market access barriers, i.e., i) invest initially in advanced production processes with the help of single-use technology, experience or outsourcing, ii) limit patent litigation, eliminate evergreening benefits, build out further the unitary patent and unified patent litigation system within the EU, iv) create demand-side policies, disseminate objective information, v) change the attitude towards biosimilar switching/substitution, starting with physician and patient education, and vi) differentiate the biosimilar by service offerings, use an appropriate comparator in cost-effectiveness analyses.A description of the players in the biopharmaceutical market and different competitive activities can be found in Part 3. The descriptive analysis in Chapter 3 shows that the top 25 pharmaceutical companies are all engaged in the biopharmaceutical market. A snapshot as of December 2016 shows in which way these companies diversify to strengthen their position in the biopharmaceutical market, i.e., via the development of originator biologicals, investment in biotechnology, development of 'next-generation' biologicals, development of biosimilars, investment in emerging countries, and collaboration between companies. The latter has been often adopted as a way to, for example, gain access to regions the company has less experience with.In Chapter 4, we investigate competition strategies related to intellectual property rights by mapping patents and patent applications for originator as well as biosimilar monoclonal antibodies in Europe. Via an analysis of case law, it was investigated to what extent patents for the originator product are a hurdle to biosimilar market entry. In addition to the basic patent and supplementary protection certificate, secondary patents (for example on a new indication, new formulation/administration form, or new dosage regime) can in some cases be a substantial hurdle for biosimilar developers to overcome, either via patent litigation cases or by inventing around the patented invention. As many of the studied cases were won by biosimilar developers, these hurdles seem surmountable, but, nonetheless, can delay market access of the biosimilar and create uncertainty on its launch date. Patent protection on biosimilars mainly pertains to new formulations.Part 4 aims to investigate and describe market entry of biosimilars. In Chapter 5, the current European regulatory framework for biosimilars is discussed, including perspectives on this framework from external stakeholders (i.e., healthcare professionals and patients), and ongoing initiatives and future developments to enhance the efficiency of the regulatory process and evolve towards a multi-stakeholder collaboration. The main challenge will be to educate physicians and other healthcare professionals on the biosimilar development pathway. For this, an active communication strategy is needed targeting physicians.In Chapter 6, we zoom in on price setting of a specific product and report for 30 European countries list prices of originator adalimumab (world's best selling medicine) before and after loss of exclusivity in October 2018, changes in reimbursement status of adalimumab products following the introduction of biosimilars, and relevant national policy measures. When disclosed by the survey participants, actual prices are presented for originator adalimumab after loss of exclusivity (11 of the 30 countries). List prices and actual prices varied widely between countries and in general decreased after loss of exclusivity. However, in some countries, six months after loss of exclusivity, the list price of originator adalimumab was still the same. A limited number of countries has made changes to the reimbursement status of adalimumab products after the entry of biosimilars. Also, only few countries adopted specific polies and practices for (biosimilar) adalimumab, although more general measures regarding biosimilars might already be implemented.In Chapter 7, we explore methodological issues for economic evaluation of biosimilars in the context of reimbursement of biosimilars. When the reference product is reimbursed, it is not deemed necessary to conduct an economic evaluation, but rather a comparison of prices. If the reference product is not reimbursed for a specific population or indication, or is not the standard of care, a full economic evaluation (e.g. cost-effectiveness, cost-utility or cost-benefit analysis) of the biosimilar versus the standard of care is recommended. Also in case of differences in administration form or adherence, or to take into account value-added services, a full economic evaluation might be needed. As only few national guidelines of HTA bodies and reimbursement agencies address these different cases, we recommend that clear guidance is developed on how to assess the value of a biosimilar. It can be argued that even if an economic evaluation can be useful for a biosimilar, this entails an extra cost and time investment, which might challenge pricing of the biosimilar and early competition.In Part 5, the European biosimilar policy landscape is described, and starts with an overview of biosimilar policies in 24 European countries in Chapter 8. In most countries, specific supply-side policies for biosimilars were in place. However, few countries have adopted demand-side policies to stimulate the use of biosimilars. These policies are mainly limited to educational initiatives for physicians, and entail to a lesser extent incentives for other healthcare professionals.In Chapter 9 and 10, regional market dynamics of originator and biosimilar infliximab (hospital setting) and etanercept (outpatient setting) are presented for the 21 counties of Sweden. Furthermore, it is examined how these market dynamics are influenced by local policy measures and practices, in addition to national policy. Market shares of biosimilar infliximab and etanercept varied widely between the Swedish counties. For infliximab, a simple linear regression analysis for the year 2017 showed that 59% of the variability in biosimilar market shares could be explained by the relative difference in discounted price between biosimilar and originator product. For etanercept, prices are coordinated on a national level and any differences in biosimilar uptake suggest that counties react differently to the estimated limited price difference between biosimilar and originator product. In addition to the influence of the price difference, the presence of key opinion leaders, local guidelines and how savings will be distributed among stakeholders, appeared to play a role in originator/biosimilar market dynamics for both molecules. To facilitate the implementation of policy measures, enabling factors such as a multi-stakeholder approach, an altruistic attitude and good communication between colleagues could be identified.In Chapter 11, we discuss Belgium as an example of a country with low biosimilar uptake. Although achieving high biosimilar market shares is not necessarily a goal in itself, as cost savings in Belgium are also realised by mandatory price reductions on originator medicines, we believe that biosimilars are essential to ensure the long-term sustainability of the off-patent biologicals market. Several ad hoc measures have been adopted to increase competition in the Belgium's off-patent biologicals market. However, we suggest that all stakeholders develop a long-term coherent, integrated policy framework that is built on the following four pillars: i) the creation of a proactive and transparent climate supporting a level playing field for both biosimilar and reference product, ii) investment in educational activities, including raising awareness of societal responsibility iii) enforcement of the practical implementation of public procurement law, and iv) development of physician incentives. Finally, in Part 6, we formulate recommendations supporting a long-term sustainable biologicals market in the presence of biosimilars (Chapter 12). The concluding discussion puts forward eight recommendations: i) Develop a coherent policy framework with multi-stakeholder involvement, ii) Reduce hurdles related to patents to ensure timely biosimilar market entry, iii) Establish an active communication strategy on regulatory aspects targeting healthcare professionals and patients, iv) Look at actual prices rather than list prices when studying price effects, v) Implement pricing and procurement systems that stimulate competition, vi) Implement a tailored approach to economic evaluation of biosimilars, vii) Invest in educational activities, and viii) Create demand-side policies.Future research should focus on new players on the market, shifts from biosimilar and reference product to newer innovative therapies, identification of factors affecting competition and sustainability of the market, and physicians' behaviour in adopting of new medicines.

Jaar van publicatie:2020