Review Calls for Path to Global Harmonization of Biosimilar Development Regulations

Global harmonization of biosimilar regulations will enhance development and patient access, but overcoming technical and regulatory hurdles will be essential to achieving this goal, according to authors of a review published in Therapeutic Innovation & Regulatory Science.¹

With estimates suggesting that by 2027, 55% of off-patent biologics may lack biosimilar competition, the lack of regulatory convergence threatens affordability, health care budgets, and supply security. | Image credit: Planetz - stock.adobe.com

This review was conducted to address the growing need for global biosimilar regulatory harmonization, as conflicting requirements increase development costs, delay approvals, and limit patient access. Since the European Union established the first biosimilar framework in 2004, many countries have adopted similar regulations, but key differences remain in areas like reference product sourcing, clinical study requirements, and labeling. Although guidelines from the World Health Organization (WHO) have supported alignment, some jurisdictions still treat biosimilars like generics or novel drugs, creating inefficiencies.

With estimates suggesting that by 2027, 55% of off-patent biologics may lack biosimilar competition, the lack of regulatory convergence threatens affordability, health care budgets, and supply security.² By analyzing biosimilar guidelines in over 70 countries, this review identifies regulatory disparities, their impact, and strategies to achieve global harmonization.

Researchers identified biosimilar regulations and guidelines from 68 countries across 7 regions by searching health authority websites, pharmaceutical trade associations, and databases managed by the Generics and Biosimilars Initiative and The Center for Biosimilars^®. They examined whether countries had a single biosimilar guidance, multiple guidelines, or a separate legal framework, while also noting those without distinct biosimilar regulations.

Only regulatory documents and scientific publications published between 2019 and 2024 were assessed for biosimilar approval requirements, focusing on local comparability and toxicology studies, clinical study design, local patient data, and labeling differences.

Biosimilar regulatory frameworks across various countries and regions consistently recognize that biosimilars must match the key characteristics of their reference biologic. Analytical assays serve as the foundational level of evidence, incorporating chemical, biochemical, biophysical, and biological function methodologies. While there are variations in the rigor and extent of analytical comparisons across jurisdictions, these differences stem from individual health authorities rather than the fundamental biosimilar concept itself.

In most countries, biosimilars undergo direct comparisons with reference biologics in all key studies. However, a few countries allow an alternative pathway where copy biological drugs are designed to match reference biologics but are not evaluated in head-to-head comparisons. Although these copy biologics may be safe and effective, they should not be categorized as biosimilars.

A review of biosimilar regulations across multiple countries identified 5 key areas of regulatory variability:

1. Analytical and clinical comparability against locally sourced reference products
2. Requirements for animal toxicology studies
3. Design of pivotal clinical studies
4. Necessity for clinical data from a local patient population
5. Format of the product label or monograph

Global Variability in Biosimilar Regulatory Requirements

While some countries initially required local reference products for biosimilar comparisons, global studies have shown minimal differences between regions. Regulators like the European Medicines Agency (EMA) and Health Canada now accept nonlocal reference products, although countries like the Republic of Korea, Japan, and the US still mandate analytical bridging studies, adding complexity for manufacturers.

Once a standard requirement, animal toxicology studies are now widely recognized as unnecessary for biosimilars. The FDA and EMA favor in vitro bioassays, but countries like Brazil, China, and the Republic of Korea still require animal testing. The FDA Modernization Act of 2022 officially removed the animal testing mandate in favor of broader nonclinical assessments.

Biosimilar clinical study requirements differ globally, with some regulators accepting surrogate pharmacodynamic biomarkers while others demand traditional phase 3 trials. Postmarketing safety monitoring expectations also vary. The differences between the FDA and EMA approval processes for Sandoz’s filgrastim biosimilar highlight these regulatory inconsistencies.

The review highlighted the challenges of achieving a single global standard, arguing that even partial harmonization could significantly streamline development. Regulatory science initiatives, including the WHO’s revised guidelines, showed progress in eliminating unnecessary clinical efficacy studies, but national agencies’ preference for independent decision-making and limited data sharing remained barriers.

Beyond regulatory alignment, biosimilar adoption is also shaped by policy dynamics. Countries like Canada and Germany promoted uptake through mandatory switching from originators to biosimilar options and benefit-sharing, while US market tactics—such as bundling, rebates, and product-hopping—created barriers.³

Despite the challenges posed by smaller health authorities and the time needed for global consensus, the authors emphasized that harmonization could significantly lower development costs and improve patient access.

“In the long term, the global harmonization of some or all biosimilar requirements and guidelines will speed and lower the cost of development leading to better patient access to these biological drugs and will help make health care more affordable without compromising safety and effectiveness. The sustainability of products in a national market is equally important but separate, and ultimately will ensure that patients have access to these important medication alternatives.”

References

1. Kirchlechner TM, Cohen HP. Global harmonization of biosimilar development by overcoming existing differences in regional regulatory requirements - outcomes of a descriptive review. Ther Innov Regul Sci. 2025;59:245-255. doi:10.1007/s43441-024-00740-4

2. Jeremias S. The biosimilar void: 90% of biologics coming off patent will lack biosimilars. The Center for Biosimilars. February 5, 2025. Accessed March 14, 2025. https://www.centerforbiosimilars.com/view/the-biosimilar-void-90-of-biologics-coming-off-patent-will-lack-biosimilars

3. Jeremias S. Skyrizi overtakes Humira: “product hopping” leaves biosimilar market in limbo. The Center for Biosimilars. November 7, 2024. Accessed March 14, 2025. https://www.centerforbiosimilars.com/view/skyrizi-overtakes-humira-product-hopping-leaves-biosimilar-market-in-limbo