Ensuring the safety, quality, and efficacy of biosimilars is essential to garnering confidence in these cost-saving medicines by both physicians and patients. A strong regulatory framework is thus essential to avoiding the introduction of poor-quality biosimilars that lack strong data supporting their similarity to the original (reference) product. At present, some countries around the world have long-established, mature, and robust regulatory pathways for biosimilar approval, while others have strong regulations in place but are not yet experienced in implementing or evaluating biosimilars. Still other countries have guidelines that reference the regulations from these countries but only weak regulatory frameworks in place or none at all. Differences among the mature pathways further compound the challenges associated with launching biosimilar products into many markets. The added time and cost not only reduce patient access — they inhibit further innovation.
The Critical Role of Biosimilar Approval Pathways
Small molecule medicines are created from chemicals with well-defined molecular structures. Although there are requirements, such as in vivo bioequivalence studies for these compounds, verifying whether a generic version has the correct active substance and similar behavior from the reference product that has already been tested and approved is much simpler than it is for biological products. In addition to understanding the kinetic behavior of generics, another major challenge in obtaining approval for small molecule generics is to ensure that no new potentially harmful impurities are introduced through the various routes of synthesis.
In contrast, biologic drugs are complex and consist of multiple molecular entities. Producing recombinant proteins and antibodies using living cells leads to a heterogeneous product mixture, with slight variations in protein sequences and posttranslational modifications (such as added sugars, phosphates, or other moieties). This complexity means that biopharmaceuticals require a very complex and well-characterized manufacturing process to match molecules as closely as possible in order to retain therapeutic action. It is also important to note that even the inter-batch variability of an innovator product effectively presents the same difficulties — no two batches of innovator products are the same, only similar to one another.
As mentioned, it is possible to develop and manufacture biosimilars, which are products that closely resemble the original biologic drug in terms of physicochemical properties, pharmacokinetics, safety, and efficacy. Regulatory approval pathways that mandate extensive characterization and demonstration of in vitro and in vivo performance, including relevant human clinical studies, are crucial. These pathways ensure that biosimilars introduced to the market exhibit sufficient similarity to their reference products, guaranteeing safety and efficacy for patients.
Limited International Harmonization
One of the greatest challenges to the growth of the biosimilars market — and thus to greater access to safe, life-changing medicines worldwide — is the lack of standardized regulations for the development and approval of biosimilar products. While there are international guidelines that provide recommendations for high-quality and safe product development, such as the World Health Organization (WHO), the European Medicines Agency (EMA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, differences in regulatory implementation from country to country lengthen timelines, increase costs, and ultimately stifle innovation and limit patient access to medicines.1
The first biosimilar approval pathway was introduced in Europe in 2006, and this region continues to lead with the highest number of approvals. The United States did not establish its regulatory pathway until 2009. It took another six years before the first biosimilar was approved in the country, and the United States continues to lag behind Europe (53 approved biosimilars in the United States vs. 86 in Europe as of the end of June 2024).2 Changes are occurring, though. A record eight biosimilars were approved by the U.S. Food and Drug Administration (FDA) in the first half of 2024, and the agency announced the Biosimilars Action Plan, which aims to streamline the development of biosimilars.
However, significant differences remain in the approaches to biosimilars taken by the EMA and the FDA, making it difficult to achieve harmonization between the two agencies, despite the hard work that has been ongoing for more than six years. While both agencies require a thorough scientific assessment to determine the similarity of the biosimilar candidate to the originator product, once approved by EMA, biosimilars can be automatically substituted for branded drugs by physicians and pharmacists. In the United States, additional requirements (switching studies) must be met for biosimilars to be considered interchangeable with the originator drugs.3 Each state has also passed legislation regarding the interchangeability of biosimilars, with some forbidding it. The Biosimilar Red Tape Elimination Act, first introduced in the U.S. Senate in 2022 and again in 2023, seeks to harmonize U.S. regulations with those of the EMA regarding automatic interchangeability. No action has been taken on it to date.
The World Health Organization (WHO) published initial guidelines on the evaluation of “biologically similar biotherapeutic products” in 2009. These recommendations were updated in 2022 and include renaming biosimilars as “biological products that are highly similar” to well-characterized reference products.4 There is notable variation in the terminology surrounding biosimilars in regulations passed by different countries. While the term “biosimilars” is used in the EU, United Kingdom, United States, China, and a handful of other countries, terms including “biosimilar products,” “similar biologics,” “similar biological medicinal products,” “follow-on biologics,” and “bioanalogues” have been employed by various regulatory bodies.1
Most countries have modeled their biosimilar regulations after those developed by the WHO, EMA, and/or FDA or recommend that any biosimilars submitted for approval have already received marketing authorization by the EU or U.S. agencies. However, discrepancies exist.1 Both “comparability” and “similarity” are used when discussing the comparison of the properties of a biosimilar candidate and its reference products. Criteria that must be met to allow extrapolation of a biosimilar approval from an initial indication to others differ from country to country. As exemplified by EU and U.S. regulations, definitions and requirements for interchangeability also vary. Guidance regarding the selection of the reference product can be ambiguous, and some require the use of in-country products. Differences also exist with regard to application fees and patent protection.
Regulatory Pathways in Mexico and Canada
Canada is considered to have a mature biosimilar approval pathway.5 In Canada, biosimilars are approved according to a science-based regulatory framework that requires the demonstration of comparative quality and performance, ensuring highly similar structure, function, efficiency, and safety to the reference product, including evidence of no clinical differences.6 Interchangeability is determined by individual provinces.
In Mexico, biocomparables were first mentioned in drug regulations in 2011.7 The General Health Law Regulations of Mexico define biocomparables as being comparable to reference products regarding safety, quality, and efficacy. Initially, the Federal Commission for Protection against Sanitary Risk (COFEPRIS) granted some marketing authorizations to biolimbos, non-innovator biologics not supported with data demonstrating equivalent quality, safety, and efficacy. Currently, NOM-257-SSA1-2014 concerning biologics (NOM 257) requires that all biolimbos undergo the appropriate review process, but some biocomparables remain on the market that have not undergone specified evaluations. As of May 2021, Mexico accepts clinical data obtained in the country of origin for initial applications, but the renewal of a marketing authorization requires clinical data collected in Mexico. Biocomparables are approved for all indications of the reference product as appropriate, and extrapolation to other indications may be possible if scientifically justified.
A Regulatory Certainty Strategy for the Pharmaceutical Sector: Biosimilars was proposed by the Mexican Ministry of Health in 2024 with the goal of promoting the development of biocomparable biologics. This will be achieved in part by establishing regulations aligned with international standards.7,8 Regulations will be aligned with the ICH and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) and the WHO guidelines on biosimilars, particularly with respect to bioequivalence and biocomparability studies. The requirement for Mexican clinical studies is also expected to be eliminated.
Regulatory Landscape in Latin America
The regulatory landscape for biosimilars in Latin America is inconsistent. Argentina and Brazil are two countries that have taken significant steps toward establishing strong approval pathways — so much so that they are the only two full members of the ICH in Latin America. However, while the trend in the region is to improve regulatory standards, internationally recognized regulatory frameworks remain lacking in many other countries.9 As a result, non-comparables, biocopies, biomimics, and non-regulated biosimilars are marketed in the region.10 Regulations also vary notably from one country to another owing to cultural, economic, and regulatory outlooks.
The Brazilian Health Regulatory Agency (ANVISA) published its initial biosimilar regulation in 2010, and by the end of 2021, had approved more than 40 biosimilar products.11 In Argentina, the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) issued a draft guideline on “medicamentos biológicos” (the term biosimilars is not used but a specific guideline refers to biologics products with previous background) in 2008, which was based on the EMA guidelines.12 With respect to other Latin American countries,10 Chile has had Technical Guideline Number 170 in place since 2014, which outlines the approval process for biosimilars, requiring submission of both preclinical and clinical data. There have also been three possible approval routes for biocompetitors, biosimilars, or biogenerics in Colombia since 2014. Ecuador’s 2014 regulation on biosimilar approval was updated in 2019 to align with international guidelines. Guatemala’s 2019 regulation allows the extrapolation of biosimilars approved by FDA, EMA, and recommended by WHO. In Peru, according to a 2016 decree, biosimilar approval requires submission of comparative data according to ICH requirements, and extrapolation can be applied to biosimilars approved by the FDA and EMA and recommended by the WHO.
Regulatory Framework in the Asia-Pacific Region
Within the Asia-Pacific region, the largest markets for biosimilars are China, India, and Japan. South Korea is also a leading player in biosimilar manufacturing and use. Japan was one of the earliest countries to establish a regulatory pathway for biosimilars, developing its guidelines in 2009, and continues to streamline the approval process.13 Both Japan and South Korea modeled their regulations after the EMA and FDA requirements.14
China and India developed their own regulatory pathways.14 China issued guidelines in 2015 and approved its first biosimilar in 2019, although non-approved copy-biologics had already been available in the country for many years.15 The China National Medical Products Administration (NMPA) has been working overtime to align its approval pathway for biosimilars with international regulations, since China is now a full member of the ICH as well.14,16
India’s regulations continue to evolve. A guideline was issued in 2012 and revised in 2016 to include post-marketing study requirements, but the first “biosimilar” was approved in 2000 without any specific requirements.7 In addition to not being aligned with international regulations, the guidelines in India are not legal requirements. As a result, international companies have challenged Indian biosimilar makers on several occasions, particularly regarding the legitimacy of the reference products used for comparative clinical studies.18 Taiwan and Malaysia recently developed approval guidelines for biosimilars.14
Regulatory Landscape in the Middle East and Africa
Only a few countries in the Middle East and Africa have somewhat mature and established biosimilar approval pathways. This inconsistency makes introducing biosimilar products into the region quite challenging.
For instance, there are 54 countries on the African continent, and each has its own regulatory authority. Only South Africa has an established framework (first issues in 2014) for biosimilar approval.19,20 Tunisia’s biosimilar regulations, issued in 2018, refer directly to EMA, WHO, and ICH guidelines. Algeria announced it was developing draft regulations on biosimilar approval in 2018, and while it is believed a draft exists, nothing has been shared with industry (as of the end of 2023).21
Most countries in the Middle East have some level of guidance or regulations for biosimilar approvals. Saudi Arabia, Egypt, Lebanon, Jordan, Bahrain, and Iraq all have published guidelines.
The Saudi guidelines and regulations for biosimilars are covered in the regular drug approval framework, heavily referencing U.S. FDA regulations while incorporating local/regional requirements contained in the Gulf Cooperation Council (GCC) Guideline on Biosimilars issued in 2016.22 A separate guidance document (Guideline on Biosimilar Products – Quality Considerations, current version 1.0) addresses requirements for demonstrating comparability.
Egypt’s current biosimilar regulation was published in September 2023,21 primarily referencing EMA regulations.22 Imported biosimilars must meet some different requirements, including being approved and marketed in the country of origin and from certain countries; otherwise, a site inspection for GMP compliance is required. Jordan’s biosimilar guidelines were adopted in 2015 and specifically reference EMA guidelines.
Iraq has no specific biosimilar approval guidelines, but its general drug regulations refer heavily to the EMA.21 It is recommended that biosimilars have received approval in the EU, U.S., Canada, Japan, Switzerland, or Australia before registering them in the country. Lebanon issued guidance on the approval of similar biological medicinal products in 2016, following the WHO biosimilar guidelines. Bahrain issued a guideline for licensing biosimilar medicinal products in March 2023. Kuwait relies on the GCC guideline on Biosimilars from 2016. The United Arab Emirates currently has no biosimilar-specific regulations, but the UAE Ministry of Health and Prevention is developing guidance. In the meantime, imported products are required to meet U.S. FDA or EMA expectations for biosimilars.
Conclusion
Biosimilars have the potential to reduce treatment costs and increase patient access to state-of-the-art medicines. However, the lack of standardized international regulatory pathways has led to reduced efforts by drug makers to market their biosimilar products globally. Meeting vastly varying regulatory requirements across different regions adds significant time and cost to biosimilar development.
Standardization is needed in reference product sourcing and dossier preparation.5 In emerging markets, there is a significant need for additional clarification and details regarding requirements for clinical study design and the establishment of critical criteria. Differences in philosophies regarding the extrapolation of approvals for different indications and the interchangeability/switching/substitution of biosimilars further complicate compliance. The development of pediatric biosimilars is another area requiring attention.
Global harmonization of biosimilar regulatory frameworks would afford many benefits to both manufacturers and patients.1 Uniform regulatory reviews would allow the sharing of data between regulatory bodies in different countries, reducing the need for nearly duplicate testing and document preparation. Biosimilar products approved in one country could more quickly be introduced into other markets. The costs of launching biosimilars into multiple markets would also be much lower. Consequently, more biosimilars would be launched in countries around the world at reduced costs for patients, dramatically increasing access.
Achieving global harmonization of biosimilar regulations is not an easy task. It will require extensive communication and collaboration between regulatory authorities and agreement on scientific requirements for demonstrating similarity, as well as alignment on approaches to extrapolation and interchangeability, areas that are currently highly contentious. Numerous legal and intellectual property issues will also need to be addressed.
The first step, according to the international organization Act4Biosimilars, is to help countries lacking strong regulatory pathways for biosimilars develop and implement them.23 The initial focus is on Latin America and Africa, with the overall goal of increasing global biosimilar adoption from approximately 14% in 2022 by at least 30 percentage points across more than 30 countries. Countries will be encouraged to reference WHO guidelines for biosimilar approval to ensure the quality, safety, and efficacy of new products and to start working toward internationally aligned regulations.
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