Global Regulatory Harmonization for Biosimilars: Current Progress, Challenges, and Future Directions

Biological medicines, or biologics, represent a transformative class of therapeutics that have significantly improved the treatment outcomes for complex and chronic diseases such as cancer, autoimmune disorders, and metabolic conditions. Unlike small-molecule drugs, biologics are derived from living organisms and possess highly complex structures, making their manufacturing, characterization, and quality control considerably more challenging. The expiration of patents for several originator biologics has facilitated the emergence of biosimilars—biological products that are highly similar to an already approved reference product, with no clinically meaningful differences in terms of safety, purity, and potency (European Medicines Agency [EMA], 2023; U.S. Food and Drug Administration [FDA], 2024. (European Medicines Agency., 2022) [1] Biosimilars are regarded as an important solution to escalating healthcare costs, particularly in biologics-intensive therapeutic areas. However, their regulatory oversight poses unique challenges due to the scientific intricacies involved in demonstrating biosimilarity. [2] Unlike generic drugs, which require demonstration of chemical equivalence, biosimilars necessitate a comprehensive comparability exercise encompassing analytical, preclinical, and clinical evaluations (WHO, 2022). Regulatory frameworks for biosimilars have evolved over the past two decades, with pioneering guidelines issued by the EMA in 2005, followed by other major agencies such as the FDA, PMDA (Japan), Health Canada, and CDSCO (India). Although these frameworks share common scientific principles, significant divergences persist regarding data requirements, interchangeability designations, and post-marketing surveillance obligations (Ramanan & Grampp, 2014). Such inconsistencies create operational hurdles for manufacturers seeking multi-jurisdictional approvals, resulting in increased development timelines and costs. [3] Global regulatory harmonization refers to the process of aligning technical requirements, review processes, and post-approval obligations across different jurisdictions to enable more efficient and predictable pathways for drug development and approval (ICH, 2023). For biosimilars, harmonization holds promise for reducing redundancy in testing, streamlining dossier preparation, and accelerating patient access globally. This paper systematically examines the current status of biosimilar regulatory harmonization efforts, identifies the major barriers preventing alignment, and proposes strategic approaches for fostering greater convergence among global regulatory authorities. [4] threatening conditions, including cancer, autoimmune disorders, and diabetes (Blackstone & Fuhr, 2021). Due to their complexity and high manufacturing costs, biologics are often associated with substantial healthcare expenditures. Once the patent and exclusivity period of a reference biologic expires, biosimilars — highly similar versions of the original biologic with no clinically meaningful differences in safety, purity, or potency — can be developed and marketed. Biosimilars offer significant benefits, including reduced costs, increased patient access, and enhanced competition within the pharmaceutical market. According to the IQVIA Institute for Human Data Science (2022), biosimilars have generated billions of dollars in savings for healthcare systems worldwide. However, because biologics are large, complex molecules produced in living systems, biosimilars cannot be exact copies of their reference products in the same way as generic small-molecule drugs. [5] This complexity necessitates rigorous regulatory evaluation to ensure biosimilar safety, efficacy, and quality. --- 1.2 Need for Regulatory Oversight Regulatory frameworks for biosimilars have been established in numerous jurisdictions to guide their development, approval, and post-marketing surveillance. Agencies such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have developed detailed guidelines outlining requirements for analytical comparability, non-clinical studies, and clinical trials (EMA, 2022; FDA, 2023). The World Health Organization (WHO) has also published guidelines to assist countries lacking established biosimilar regulations. Despite these efforts, there remain significant differences in approval requirements, particularly concerning interchangeability, extrapolation of indications, and pharmacovigilance.1.3 Concept of Regulatory Harmonization Regulatory harmonization refers to the process of aligning technical requirements, procedures, and standards for the development, registration, and marketing authorization of medical products across jurisdictions. Harmonization aims to reduce duplication, accelerate product access, and ensure consistent quality, safety, and efficacy standards globally (Ravi et al., 2020). [6] For biosimilars, harmonization is especially critical because their development often involves multinational clinical programs and cross-border manufacturing. Organizations such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and WHO have made substantial progress toward harmonizing pharmaceutical regulations. However, biosimilars pose unique challenges, including varying national policies, differing scientific interpretation of similarity, and inconsistent interchangeability rules that impede complete convergence.1.4 Rationale for the Study While the biosimilar market has grown rapidly in high-income regions, many low- and middle-income countries (LMICs) have yet to fully implement harmonized regulatory frameworks. Disparities in regulatory expectations create inefficiencies, increase development costs, and delay patient access to affordable biologics. A systematic understanding of these differences, and of ongoing harmonization initiatives, is essential for identifying opportunities to streamline global biosimilar regulation. This study systematically reviews current biosimilar regulatory frameworks in major jurisdictions, evaluates harmonization progress, and proposes strategies to overcome existing barriers. It seeks to contribute to policy discourse by providing evidence-based recommendations for regulators, policymakers, and industry stakeholders. [7]

LITERATURE REVIEW: -

2.1 Evolution of Biosimilar Regulation

The concept of biosimilars was formally introduced in the European Union (EU) in 2005 when the EMA approved Omnitrope® (somatropin) as the first biosimilar product under a dedicated regulatory pathway (EMA, 2005). This milestone was preceded by extensive scientific debate on the comparability exercise — the process of demonstrating that a biosimilar is “highly similar” to its reference biologic in terms of structure, function, and clinical performance (Schellekens, 2009).[8] The United States followed with the Biologics Price Competition and Innovation Act (BPCIA) of 2009, which created an abbreviated pathway for biosimilars and interchangeable products (FDA, 2010).In parallel, the WHO published its “Guidelines on Evaluation of Similar Biotherapeutic Products” in 2009 to support countries lacking established biosimilar regulations (WHO, 2009). These guidelines have since served as a foundation for national frameworks in multiple low- and middle-income countries, including India, Brazil, and South Africa (Rugo et al., 2021). [9]

 2.2 Scientific Basis for Regulatory Requirements:

Unlike generic small-molecule drugs, biosimilars are complex macromolecules produced in living cells, which introduces inherent variability. As such, the regulatory approval process for biosimilars focuses on the totality of evidence approach — an assessment that integrates analytical, non-clinical, and clinical data to establish similarity to the reference product (McCamish & Woollett, 2012). Analytical characterization is considered the cornerstone of biosimilar development, involving comparative studies of physicochemical properties, biological activity, and structural attributes using state-of-the-art techniques such as mass spectrometry and X-ray crystallography (Vulto & Jaquez, 2017).[10] Non-clinical studies may include in vitro assays and animal models to assess toxicity, although many regulators now accept limited non-clinical programs if robust analytical data are available (EMA, 2022; FDA, 2023). Clinical requirements typically involve at least one comparative pharmacokinetic/pharmacodynamic (PK/PD) study and a confirmatory phase III equivalence trial in a sensitive patient population (Blackstone & Fuhr, 2021). However, the scope and size of clinical trials required differ substantially among jurisdictions. [11]

2.3 Divergence Among Regulatory Agencies: -

Despite a shared scientific foundation, biosimilar regulatory pathways exhibit differences that can hinder global development. The EMA and WHO generally accept extrapolation of indications — the approval of a biosimilar for all indications of the reference product based on evidence from one or more clinical settings — if justified by the totality of evidence (EMA, 2022; WHO, 2022). In contrast, some countries, such as Japan and Canada, impose additional clinical requirements for certain extrapolated indications (PMDA, 2021; Health Canada, 2020). Interchangeability: - the ability to substitute a biosimilar for its reference biologic without prescriber intervention is another area of divergence. In the U.S., the FDA grants interchangeability status separately from biosimilar approval, requiring additional switching studies (FDA, 2023). The EMA, on the other hand, leaves interchangeability decisions to individual member states (EMA, 2022). This regulatory fragmentation increases development costs and delays multinational market entry. [12]

2.4 Global Harmonization Initiatives: -

Harmonization efforts are being pursued by several international bodies. The International Council for Harmonisation (ICH) has developed guidelines relevant to biologics quality (e.g., ICH Q5E on comparability of biotechnological/biological products) and clinical requirements (ICH E5 on ethnic factors in clinical trials), which indirectly support biosimilar alignment (ICH, 2022). The WHO has initiated collaborative registration procedures that allow simultaneous evaluation of biosimilar dossiers by multiple national regulatory authorities, reducing time to approval (WHO, 2021). Regional harmonization programs, such as the African Medicines Regulatory Harmonization (AMRH) initiative, also aim to streamline biosimilar registration in resource-limited settings (Ndomondo-Sigonda et al., 2021). [13] Nevertheless, practical implementation remains challenging due to disparities in regulatory capacity, legal frameworks, and political priorities (Ravi et al., 2020). Literature consistently emphasizes the need for greater transparency, capacity building, and mutual recognition agreements (MRAs) to achieve meaningful global convergence.  While substantial academic and regulatory literature exists on biosimilar development, few studies have comprehensively compared harmonization progress across high-, middle-, and low-income countries. Moreover, existing research often focuses on the scientific aspects of similarity assessment rather than policy-level integration. This study addresses this gap by combining a systematic review of regulatory guidelines with a comparative policy analysis, offering actionable recommendations for stakeholders. [14]

METHODOLOGY

3.1 Study Design

This study adopted a systematic review and comparative policy analysis approach to evaluate the current state of biosimilar regulatory harmonization globally. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (Page et al., 2021), ensuring methodological transparency and reproducibility. The study combined qualitative synthesis of published literature with analysis of primary regulatory documents from leading national and international agencies. [15-16]

3.2 Data Sources

Data were obtained from three primary sources:

1. Scientific Literature – Peer-reviewed articles were retrieved from PubMed, Scopus, and Web of Science using the search terms:

1)“biosimilar regulation”

2)“regulatory harmonization”

3)“biologics approval pathway”

4)“interchangeability biosimilar”

2. Regulatory Guidelines – Official documents were sourced from regulatory agencies, including:

• United States Food and Drug Administration (FDA)
• European Medicines Agency (EMA)
• Pharmaceuticals and Medical Devices Agency (PMDA, Japan)
• Central Drugs Standard Control Organization (CDSCO, India)
• Health Canada
• World Health Organization (WHO)

International Harmonization Bodies: -Guidelines from the International Council for Harmonisation (ICH) and regional initiatives such as the African Medicines Regulatory Harmonization (AMRH) program. [17]

3.3 Inclusion and Exclusion Criteria

Inclusion Criteria:

• Publications and guidelines from 2005–2025
• Documents in English
• Literature explicitly addressing biosimilar regulatory pathways or harmonization
• Policy papers, systematic reviews, and official regulatory guidelines

Exclusion Criteria:

• Non-English documents without an official translation.
• Editorials or opinion pieces lacking primary data. Studies focused solely on clinical outcomes without a regulatory context.

Regulatory landlaysis landscope analysis

4.1 Overview

Biosimilar regulatory frameworks are now established in most high-income countries and many middle-income countries, with WHO guidelines serving as a model for global adoption. However, implementation differs in terms of scientific requirements, clinical trial expectations, and policy on interchangeability. These differences can create inefficiencies for multinational biosimilar development programs and delay patient access. [18-19]

4.2 United States – Food and Drug Administration (FDA)

The U.S. pathway for biosimilars was established under the Biologics Price Competition and Innovation Act (BPCIA) of 2009 (FDA, 2010). Approval is based on the "totality of evidence," requiring stepwise demonstration of similarity through analytical, non-clinical, and clinical studies. The FDA distinguishes between biosimilar and interchangeable products, with interchangeability requiring additional switching studies (FDA, 2023). Data exclusivity for reference products is 12 years, and biosimilar applications may be filed after 4 years from the first licensure.

4.3 European Union – European Medicines Agency (EMA)

The EMA pioneered biosimilar regulation in 2005 (EMA, 2005) and remains the global reference point for scientific requirements. EMA guidelines emphasize analytical comparability and allow extrapolation of indications if scientifically justified. Interchangeability policy is left to individual member states, but the EMA recently issued a positive scientific opinion supporting interchangeability under certain conditions (EMA, 2022). Data exclusivity for reference products is 8+2 years (market plus data protection).[20]

4.4 World Health Organization (WHO)

The WHO’s Guidelines on Evaluation of Similar Biotherapeutic Products (2009, revised 2022) provide a flexible framework adaptable to resource-limited settings (WHO, 2022). WHO emphasizes the importance of a stepwise comparability exercise and accepts reduced clinical data if analytical similarity is well demonstrated. The WHO also coordinates the Collaborative Registration Procedure (CRP) to accelerate biosimilar approval in multiple countries simultaneously.

4.5 Japan – Pharmaceuticals and Medical Devices Agency (PMDA) Japan's PMDA requires biosimilars to follow a development pathway similar to EMA's but often requests additional bridging studies when foreign clinical data are used (PMDA, 2021). Japan accepts extrapolation but is conservative in interchangeability policy, requiring explicit clinical justification. Reference product exclusivity is 8 years.

4.6 India – Central Drugs Standard Control Organization (CDSCO)

India’s Guidelines on Similar Biologics (2012, revised 2016) were developed in collaboration with the Department of Biotechnology (DBT). India allows reduced clinical trial requirements for biosimilars with strong analytical similarity, and extrapolation is permitted (CDSCO, 2016). However, pharmacovigilance systems are still evolving, and interchangeability is not formally recognized. [21]

4.7 Canada – Health Canada

Health Canada’s biosimilar guidelines align closely with EMA, emphasizing analytical comparability and permitting indication extrapolation if scientifically justified (Health Canada, 2020). Interchangeability decisions are made at the provincial/territorial level.

4.8 Comparative Table – Key Regulatory Elements for Biosimilars

Regulatory AuthorityYear Pathway Established Interchangeability Policy Indication Extrapolation Data Exclusivity (Years) Notable Features.

FDA (U.S.) 2009 (BPCIA) requires separate switching studies for designation. Allowed if justified, 12 Distinct “interchangeable” categories.

EMA (EU) 2005 Left to member states; recent positive opinion Allowed if justified 8+2 First global biosimilar pathway.

WHO 2009 Not addressed (guidance-level only) Allowed if justified N/A           Flexible for LMIC adoption.

PMDA (Japan) 2009 Conservative; requires justification. Allowed if justified. 8 Bridging studies are often required.

CDSCO (India) 2012 No formal policy Allowed if justified N/A Reduced trial size possible.

Health Canada 2010 Provincial decision Allowed if justified 8 Strong EMA alignment. [22]

DISCUSSION & CHALLENGES

5.1 Persistent Divergence in Regulatory Approaches

Despite more than a decade of biosimilar experience worldwide, significant divergence persists across regulatory frameworks. While most agencies follow the scientific principles outlined by the WHO and ICH, differences in clinical data requirements, interchangeability policies, and post-marketing obligations remain pronounced (Rugo et al., 2021). One reason is the regulatory philosophy of each jurisdiction. [24] The FDA’s cautious stance on interchangeability reflects its emphasis on real-world switching evidence, whereas the EMA and WHO place greater weight on scientific justification and physician discretion (EMA, 2022; FDA, 2023). Similarly, Japan’s requirement for bridging studies stems from concerns about population-specific variability, even though the ICH E5 guideline provides a framework for evaluating ethnic factors without repeating extensive trials (ICH, 2022). [25]

5.2 Economic and Political Factors

Economic priorities also shape regulatory policy. In high-income markets such as the U.S. and EU, strong intellectual property protections and extended data exclusivity periods incentivize biologic innovation but can delay biosimilar entry (Blackstone & Fuhr, 2021). Conversely, emerging economies such as India prioritize affordability and market access, leading to shorter development timelines and reduced clinical requirements (CDSCO, 2016). However, these expedited pathways may raise questions about regulatory robustness in the eyes of stringent authorities, creating barriers to mutual recognition.

5.3 Case Study 1 – Trastuzumab (Herceptin® Biosimilars)

Trastuzumab biosimilars illustrate the complexity of multi-jurisdictional approvals. In the EU, the first trastuzumab biosimilar (Ontruzant®) was approved in 2017 after comprehensive analytical and clinical comparability studies in HER2-positive breast cancer (EMA, 2017). In the U.S., approval came in 2019, but interchangeability status has yet to be granted (FDA, 2019). In India, several trastuzumab biosimilars entered the market as early as 2014 with smaller clinical programs, leveraging local guidelines (CDSCO, 2016). The result was a staggered global launch, with patients in LMICs gaining earlier access but without the harmonized evidence base that would facilitate mutual recognition. [25-26]

5.4 Case Study 2 – Adalimumab (Humira® Biosimilars)

Adalimumab biosimilars faced a different challenge: patent litigation. The EMA approved the first adalimumab biosimilars in 2018 (e.g., Amgevita®), enabling immediate market entry upon patent expiry.In the U.S., legal settlements delayed biosimilar launches until January 2023 despite FDA approvals in 2016–2018 (FDA, 2023). This illustrates that harmonization of regulatory science alone cannot overcome market exclusivity strategies, highlighting the interplay between law, policy, and regulation. [26]

5.5 Scientific and Technical Barriers

Even when regulatory requirements appear aligned, practical differences in dossier format, data interpretation, and quality standards can hinder harmonization. For example, Variations in reference product sourcing rules mean developers may need to conduct bridging studies if the reference biologic was obtained from a different jurisdiction (PMDA, 2021). Different expectations for immunogenicity assessment methods can complicate data acceptance (Vulto & Jaquez, 2017). [27]

5.6 Implications for Global Harmonization

The persistence of these differences suggests that true harmonization will require more than alignment of written guidelines — it will demand mutual trust, capacity building, and policy coordination. Without these, biosimilar developers will continue to face duplicated studies, prolonged timelines, and increased costs, ultimately limiting the global public health benefits of biosimilars.

U.S. Compares to Europe on Biosimilar Approvals and Products In the Pipeline - Updated May 2, 2025

Future Outlook & Recommendations

6.1 The Road Ahead

The global biosimilar market is projected to exceed USD 75 billion by 2030 (IQVIA, 2022), making regulatory harmonization not just a technical goal but a strategic imperative for public health. A harmonized approach could shorten approval timelines, reduce development costs, and expand access to affordable biologics in both high- and low-income countries.

6.2 Strategic Recommendations for Harmonization

1. Adoption of a Core Global Standard

WHO and ICH could jointly publish a “Global Biosimilar Regulatory Template” containing baseline scientific requirements and dossier formats. This template should be binding for member states that adopt it, with flexibility for local adaptations.

2. Mutual Recognition Agreements (MRAs)

Regulatory agencies should formalize MRAs, enabling one agency’s approval to be recognized (or partially accepted) by others, particularly for analytical and non-clinical data.

U.S. Compares to Europe on Biosimilar Approvals and Products In the Pipeline - Updated May 2, 2025 3. Regulatory Capacity Building

Low- and middle-income countries (LMICs) should receive technical support from WHO, EMA, and FDA to strengthen their review capabilities, reducing reliance on duplicative trials.

4. Global Pharmacovigilance Network

Establish a centralized, real-time adverse event reporting platform for biosimilars, accessible to all participating regulators.

5. Harmonized Interchangeability Criteria

Develop a unified scientific standard for interchangeability to avoid the current “dual status” problem in the U.S. versus the EU.

6.3 Proposed Harmonization Roadmap

Phase 1 – Short Term (1–2 years)

WHO publishes the Global Biosimilar Regulatory Template. Initiate training workshops for LMIC regulators.

Phase 2 – Medium Term (3–5 years)

Launch mutual recognition pilot programs between ICH member states and selected LMICs. Implement a global pharmacovigilance database for biosimilars.

Phase 3 – Long Term (5–10 years)

Achieve broad adoption of harmonized interchangeability standards. Expand MRAs to cover the majority of biosimilar dossiers. Continuous revision of guidelines in line with technological advancements (e.g, AI-based analytical comparability). [28]

Biosimilars Targeting Pathogens [31]