The use of biosimilars and regulatory challenges worldwide

Bernadete Dias

CGM, São Paulo

bernadete.dias@cgmlaw.com.br

André Lins

CGM, São Paulo

andre.lins@cgmlaw.com.br

Thais Fernandes

CGM, São Paulo

thais.fernandes@cgmlaw.com.br

Introduction

Biosimilar medicines are biological products developed to be highly similar to an already approved biological medicine, known as a reference. Unlike generic drugs, which have a chemical composition identical to the original, biosimilars have a more complex molecular structure, subject to variations that can occur during the production process. The World Health Organization (WHO) defines biosimilars as products that have comparable quality, safety and efficacy to the reference medicine, but are not exact copies due to the complex nature of biological products.[1]

The main advantage of biosimilars is that they reduce costs for the health system because, when they enter the market, these products generate competition and provide wider access for patients to highly complex biological treatments.

Considering that the regulation of biosimilars varies widely between different jurisdictions, this article briefly presents the challenges that some markets of global relevance have faced from a regulatory point of view.

Regulation of biosimilars in Brazil

In Brazil, the regulation of biosimilars is coordinated by the Brazilian health regulatory agency Anvisa. In 2010, Anvisa established RDC No 55, which sets out the guidelines for the development and approval of biosimilars in the country. RD55/2010 requires manufacturers of biosimilars to carry out comparative quality, safety and efficacy studies to demonstrate similarity with the reference drug. These studies include rigorous clinical and pre-clinical trials.

The Brazilian standard contemplates two main paths for the approval of biosimilars:

1. Comparability route: in this route, the biosimilar undergoes extensive studies to prove its similarity to the biological reference. The evaluation process includes detailed analysis of characteristics such as structure, biological activity and stability, as well as clinical tests to ensure efficacy and safety.
2. Individual development route: here, the manufacturer can develop the biosimilar based on pre-existing data, but still needs to prove the quality, safety and efficacy of the product. This route is less common due to high costs and the difficulty of obtaining robust pre-existing data.

The approval and use of biosimilars in Brazil faces specific challenges. The production of biosimilars is more complex than that of generic drugs, requiring advanced equipment and highly qualified personnel, as well as rigorous quality control processes. Anvisa still faces difficulties in assessing companies’ technical compliance.

However, the production of biosimilars requires sophisticated infrastructure, and the lack of incentives to develop this infrastructure in Brazil has limited the number of local manufacturers.

Finally, another important regulatory challenge is the interchangeability of biosimilars with their respective reference products. In Brazil, there are no clearly defined guidelines on the automatic substitution of biologicals for biosimilars in pharmacies, which can make it difficult for healthcare professionals to adopt them.

International landscape and challenges

The regulation of biosimilars varies widely in different jurisdictions, such as the European Union, the United States and other markets of global relevance.

The EU, for example, is considered a pioneer in regulating biosimilars. Since 2006, the European Medicines Agency (EMA) has approved several biosimilars, with rules that prioritise safety and efficacy, while maintaining the need for comparative clinical trials. The EMA also defines clear rules on interchangeability and traceability, requiring each batch of biosimilars to be traceable from the producer to the patient. European experience shows that the introduction of biosimilars has led to a significant reduction in prices and increased access to biological treatments.[2]

In the US, the regulation of biosimilars is conducted by the Food and Drug Administration (FDA), which introduced the Biologics Price Competition and Innovation Act (BPCIA) of 2009. This legislation created an approval pathway for biosimilars and interchangeable biological drugs. The FDA also requires proof of biosimilarity through a rigorous comparability process and demands safety, efficacy and purity data. However, one point of difference is interchangeability, an additional designation that only some biosimilars receive, allowing them to be automatically substituted for the biological reference without intervention of the physician.[3]

In countries such as Canada,[4] Japan[5] and Australia,[6] biosimilars regulations follow similar trends to those of the EMA and FDA, adapting according to local resources and needs. In emerging markets such as India[7] and China,[8] the regulation of biosimilars is still under development. These countries face additional challenges, such as the lack of advanced infrastructure for production and testing.

Common challenges in the global development and regulation of biosimilars

There are common challenges that impact the development and regulation of biosimilars around the world. The production of biosimilars requires precision and strict process control. Small variations in manufacturing can have a direct impact on the safety and efficacy of the product, which increases costs and development time.[9]

Further, the requirement for extensive comparative studies increases the cost and time to approve new biosimilars. Although they are more affordable alternatives to the biological reference, the development process is still costly.

Another challenge is replacing a biological reference with a biosimilar without medical intervention. Many countries still have strict restrictions and regulations for this practice, which can limit patient access and adoption by physicians.[10]

Biosimilars also face barriers due to the complexity of patents on biological products. In the US, patents can be a barrier to the launch of biosimilars, while in Brazil, the lack of clarity in intellectual property rights over biosimilars also creates challenges for manufacturers.[11]

The regulatory scenario for biosimilars presents a set of legal opportunities and challenges that involve, among other things, understanding local and international legislation and mastering issues related to intellectual property and compliance. When investing in biosimilars, the pharmaceutical industry needs specialised legal support to conduct registration processes with regulatory agencies, as well as advice on issues such as patents, taxation and regulatory compliance.

The legal sector must also be aware of interchangeability issues and the impact of traceability and pharmacovigilance guidelines. The traceability of medicines, for example, requires the implementation of systems that allow monitoring at all stages of the production, distribution and use chain.

The global trend indicates that biosimilars will play a central role in reducing the costs of treatments for complex diseases such as cancer and autoimmune diseases. However, to ensure that these drugs fulfil their potential, it is crucial that regulations continue to evolve.[12]

Conclusion

The use of biosimilars is a promising strategy for expanding access to biological medicines and reducing public health costs. However, the technical and regulatory complexity surrounding the development and approval of these drugs still represents a considerable challenge. In Brazil, regulation by Anvisa is fundamental to establishing safety and efficacy standards, but faces challenges such the lack of incentives to develop infrastructure, approval times and a lack of clarity on interchangeability.

Globally, the harmonisation of standards for biosimilars could foster advances and speed up the availability of these products for patients around the world. For professionals in the legal sector and the pharmaceutical industry, in-depth knowledge of the regulations and technical aspects of biosimilars is essential to navigate successfully.

References

Anan Jarab, Shrouq Abu Heshmeh and Ahmad Al Meslamani. ‘Bridging the gap: The future of biosimilars regulations’ (2024), 20(1) Human Vaccines & Immunotherapeutics,  available at www.tandfonline.com/doi/full/10.1080/21645515.2024.2362450#abstract.

Arnolg Vulto and  Orlando Jaquez, ‘The process defines the product: what really matters in biosimilar design and production?’ (2017), Rheumatology. Available at

https://pmc.ncbi.nlm.nih.gov/articles/PMC5850795/.

Bruna de Oliveira Ascef, Renan Gonçalves Leonel da Silva, Haliton Alves de Oliveira Júnior and Patrícia Coelho de Soárez, ‘Interchangeability and substitution of biosimilars: is health technology assessment (HTA) a tool for decision-making?’ (2019), Cadernos de Saúde Pública. Available at:

www.scielo.br/j/csp/a/PVGvNzjnB5fQmYS7RCYDwmc/?lang=en&format=pdf.

Hye-Na Kang, Robin Thorpe et al, ‘Regulatory challenges with biosimilars: an update from 20 countries’ (2020), Ann N Y Acad Sci, 42. Available at https://pmc.ncbi.nlm.nih.gov/articles/PMC8247359/#:~:text=Despite%20this%20effort%2C%20a%20recent,difficulties%20with%20the%20practice%20of.

Jayne Hornung, ‘Navigating the Biosimilar Frontier: Opportunities and Challenges in 2024’ (AJMC, 14 January 2024), available at www.ajmc.com/view/navigating-the-biosimilar-frontier-opportunities-and-challenges-in-2024.

Skylar Jeremias, ‘Breaking Down Biosimilar Barriers: The Patent System’(Center for Biosimilars, 11 November 2024), available at

www.centerforbiosimilars.com/view/breaking-down-biosimilar-barriers-the-patent-system.

Skylar Jeremias, ‘Revolutionizing Biopharmaceuticals: The EU’s Biosimilar Success and Remaining Challenges’. (Center for Biosimilars, 16 October 2024). available at:

www.centerforbiosimilars.com/view/revolutionizing-biopharmaceuticals-the-eu-s-biosimilar-success-and-remaining-challenges.

Timo Minssen, ‘Biosimilars – A European perspective’ (Center for Advanced Studies in Bioscience Innovation Law, 2018), available at: https://researchprofiles.ku.dk/en/publications/biosimilars-a-european-perspective.

Veronica Salib, ‘Top Challenges Facing Biosimilar Adoption and Manufacturing’ (Techtarget, 2023), available at: www.techtarget.com/pharmalifesciences/feature/Top-Challenges-Facing-Biosimilar-Adoption-and-Manufacturing.