Toward Regulatory Convergence and Streamlined Biosimilar Development: Recommendations from an International Qualitative Study

Abstract

Objectives

This study aims to assess perspectives of stakeholders on scientific and regulatory challenges associated with biosimilarity demonstration and to formulate consensus-based recommendations to foster regulatory convergence and streamline biosimilar development globally.

Methods

A modified Nominal Group Technique with an international panel of regulators, academics, and industry representatives involved three phases: (i) first individual grading, (ii) focus group discussions, and (iii) second individual grading. High consensus was defined as ≥80% agreement with a weighted mean score of ≥ 4.0.

Results

Overall, four focus groups were held in September 2023 with 21 participants (2 academics, 7 regulators, and 12 industry representatives). In total, 22 recommendations were proposed, with 16 obtaining high consensus. Highest-rated recommendations included enhancing stakeholder education on science-based biosimilarity principles (mean score: 4.65/5), promoting regulatory convergence through reliance (mean score: 4.65/5), aligning regulatory requirements based on current scientific knowledge (mean score: 4.60/5), reconsidering the requirement for comparative clinical efficacy studies (mean score: 4.65/5), harmonizing reference product selection criteria (mean score: 4.55/5), facilitating proactive knowledge sharing among regulators (mean score: 4.50/5), eliminating in vivo animal studies (mean score: 4.50/5), and accepting clinical studies conducted for global submissions (mean score: 4.50/5). Two recommendations received the lowest consensus: providing incentives for the development of new pharmacodynamic biomarkers (mean score: 2.80/5) and developing distinct International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines for biosimilar assessment (mean score: 3.20/5).

Conclusions

The consensus-based recommendations identified in this study outline priority areas and measures for streamlining biosimilar development and fostering regulatory convergence.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40259-025-00746-w.

Key Points

Biosimilars are more-affordable alternatives to innovator biologics, which have transformed treatments for chronic and life-threatening diseases. However, regulatory requirements that are not aligned with current scientific evidence and analytical advancements present challenges in achieving global regulatory convergence and streamlined biosimilar development.

In this study, we explored expert stakeholder perspectives on current scientific and regulatory challenges associated with biosimilarity demonstration and formulated recommendations to streamline biosimilar development while promoting regulatory convergence across jurisdictions.

We identified 16 high-consensus recommendations, supported by key stakeholders, such as enhancing stakeholder education, leveraging reliance mechanisms to align global biosimilar regulatory frameworks, reconsidering the necessity of comparative clinical efficacy studies, harmonizing reference product selection criteria, and eliminating in vivo animal and local clinical studies.

The consensus-based recommendations provide the opportunity to establish science-based, harmonized, and risk-adapted regulatory frameworks for biosimilar development and evaluation, potentially reducing development costs and timelines, and increasing patient access to biologics worldwide.

Introduction

Biologics have transformed the treatment of life-threatening and chronic diseases, including cancer, diabetes, and immune-mediated inflammatory diseases. However, their increased utilization and high costs impose significant financial pressure on healthcare systems and patients. Biosimilars, biological medicines highly similar to an already licensed reference product (RP) in terms of quality, safety, and efficacy, offer a more cost-effective alternative to alleviate these financial burdens [1, 2].

Biosimilars are approved under the same rigorous standards of quality, safety, and efficacy that apply for originator biologics. The scientific foundation for biosimilar development is based on comparability studies, as defined by the ICH Q5E guideline, which outlines requirements for assessing manufacturing changes in biologics to ensure consistency in quality, safety, and efficacy [3]. Building on this, the European Medicines Agency (EMA) pioneered the development of a dedicated regulatory pathway for biosimilars in 2004 under Directive 2004/27/EC, paving the way for other countries, such as Japan, USA, and Canada, as well as the WHO to establish a regulatory framework for biosimilar evaluation and approval [4–8]. The demonstration of biosimilarity requires a rigorous, head-to-head comparison between the RP and biosimilar candidate on the basis of the “totality of evidence” approach, which comprises (i) analytical studies as the cornerstone, (ii) comparative nonclinical studies, (iii) and comparative clinical studies including clinical pharmacokinetic (PK) studies in healthy volunteers (or, in some instances, patients), pharmacodynamic (PD) studies when applicable or possible, and, where necessary, confirmatory comparative clinical efficacy studies in patients [9].

Since the approval of the first biosimilar (Omnitrope^®) by the European Commission in 2006, regulatory frameworks have continued to evolve, informed by the accumulated experience with biosimilar evaluations and ongoing reflection on the evidentiary requirements that provide the most appropriate data for decision-making [10, 11]. Although implemented at different times, regulatory frameworks for biosimilar evaluation and approval among advanced regulatory authorities exhibit a notable alignment, adhering to fundamental scientific principles for establishing biosimilarity [3, 10, 12]. While regulatory authorities are adopting more flexible and tailored approaches to biosimilar evaluation in line with scientific advancements, divergent requirements across regions have been reported to complicate the development pathway, potentially resulting in duplicative processes and unnecessary testing, increased demand for resources, and longer development timelines [13, 14]. Additionally, various factors such as the high costs associated with sourcing of the RP, extensive comparative clinical efficacy studies when scientifically unjustified, and limited commercial incentives for biosimilars targeting low-sales biologics, have been reported in the literature as impacting biosimilar development [15, 16]. These challenges are considered to contribute to increased financial burden on healthcare systems, limit patient access to quality-assured biologics globally, and concerns about the long-term sustainability of the biosimilar market.

Regulatory authorities play a critical role in fostering a feasible and supportive environment for biosimilar development, evaluation and approval. In this context, regulatory convergence aims to align regulatory processes across jurisdictions in a practical and flexible manner, without necessitating complete uniformity in standards [17]. By eliminating unnecessary requirements while safeguarding quality, efficacy, and safety, regulatory convergence enhances the efficiency of biosimilar development and evaluation.

This study builds upon a literature review with a systematic search strategy that identified scientific and regulatory challenges associated with biosimilar development and evaluation, highlighting opportunities for regulatory convergence regarding reference product selection criteria and specific data requirements for in vivo animal studies, comparative clinical efficacy studies, and local clinical studies [18]. Building on these findings, this study aims to evaluate stakeholders’ perspectives on these challenges and develop consensus-based recommendations to promote regulatory convergence and streamline biosimilar development.

Methods

Study Design

This study employed the Nominal Group Technique (NGT), a structured consensus method with four phases: (i) silent idea generation supported by a literature review [18], (ii) first grading of statements, (iii) focus groups, and (iv) second grading of recommendations [19]. Figure 1 illustrates the different study phases.

Fig. 1.

Overview of the different phases in the Nominal Group Technique process in this study.

Participant Selection

Participants were purposively selected for their expertise in the development or regulatory approval of biosimilars and originator biologics. Group discussions included four to seven participants allowing everyone sufficient time to express their opinions. Invitations with study details and practical considerations were emailed to prospective participants, followed by informed consent form in case of interest.

Study Phases

Phase 1: Idea Generation

The silent idea generation step was replaced by a literature review to identify scientific and regulatory challenges in biosimilar development and evaluation. These findings served as the basis for formulating statements on these challenges for Phase 2.

Phase 2: First Individual Grading

Participants (N = 21) completed an online survey (SurveyMonkey) with two sections: (i) demographics and (ii) statements categorized into seven thematic areas: (a) overarching challenges, (b) analytical studies, (c) reference product selection, (d) in vivo animal studies, (e) comparative clinical PK/PD studies, (f) comparative clinical efficacy studies, and (g) local clinical studies [20]. Statements were graded on a 5-point Likert scale (1= strongly disagree; 5= strongly agree). Open answer fields allowed participants to provide additional comments. Weighted mean scores were calculated for each statement (Online Resource 1).

Phase 3: Focus Group Discussions

Four virtual focus groups were held on Microsoft Teams in September 2023, each lasting approximately 2 h. Participants were divided into two categories, each comprising two focus groups: (1) academics with research experience in biosimilar regulatory science and regulators (four and five participants, respectively), and (2) industry-aligned experts (six participants per group), including individuals from pharmaceutical companies, as well as those from consulting and trade associations. In total, 21 participants took part in the study. Efforts were made to ensure a wide geographic representation. Discussions were facilitated by two researchers (moderator (EC) and observer (SS or AV)), starting with an overview of the study objectives and pre-identified thematic areas. Weighted mean scores and anonymized comments were presented. The moderator encouraged additional input from quieter participants while maintaining focus on the objectives.

Phase 4: Second Individual Grading

The group discussions provided a framework for a set of recommendations, categorized into: (i) general recommendations, (ii) reference product selection regarding (analytical and/or PK) bridging studies, (iii) analytical studies, (iv) non-clinical evaluation (in vivo animal studies), (v) clinical pharmacology (PK/PD), (vi) comparative clinical efficacy studies, and (vii) local clinical studies. The focus groups facilitated the identification of additional enablers and barriers beyond those derived from the initial literature review. These expert-generated inputs were incorporated into the final set of recommendations and prioritized accordingly. Of the 21 participants who attended the NGT discussions, 20 completed the second step by grading the recommendations. High consensus was defined as ≥ 80% agreement and weighted mean score of ≥ 4.0. Scores between 3.5 and 3.99 were considerate moderate, while those < 3.5 were classified as low consensus [21]. To highlight the highest-rated recommendations, an additional criterion of a weighted mean score of ≥ 4.5 was applied.

Qualitative Analysis

Group discussions were audio- and video-recorded, transcribed ad verbatim, and pseudonymized. Transcripts and notes were analyzed using NVivo (version 14) using the thematic framework analysis method by Lacey and Luff [22]. Pre-identified thematic areas were entered as nodes for deductive coding, while inductive coding allowed identifying additional (sub)themes.

Results

Demographics of Participants

Across the four NGT discussions, a total of 21 participants attended. Table 1 presents an overview of participant characteristics.

Table 1.

Demographic characteristics of the participants in this study

Participant characteristics	Number of participants (%)
Age
18–24 years	0 (%)
25–34 years	3 (14%)
35–49 years	7 (33%)
50–64 years	9 (43%)
65 years or more	2 (10%)
Region
Europe	8 (38%)
North America	7 (33%)
South America	2 (10%)
Africa	1 (5%)
Asia	3 (14%)
Australia	0 (%)
Setting of work
Regulatory agency or government authority	7 (33%)
Pharmaceutical industry	8 (38%)
Academia	2 (10%)
Other (trade organization, consulting)	4 (19%)
Years of experience
< 5 years	3 (14%)
5–10 years	1 (5%)
11–20 years	12 (57%)
20 years or more	5 (24%)

Recommendations

In total, 22 recommendations were developed, consisting of eight general (A–H) and 14 specific (1–14) recommendations. General recommendations reflect broader system-level priorities (e.g., stakeholder education, reliance mechanisms), while specific recommendations address analytical, nonclinical, and clinical parts of the biosimilarity exercise. Specific recommendations were categorized into six themes: (i) the reference product, (ii) analytical studies, (iii) nonclinical evaluation, (iv) clinical pharmacology studies, (v) comparative clinical efficacy studies, and (vi) local clinical studies. Of these 22 recommendations, 16 obtained high consensus, four moderate consensus, and two low consensus. Table 2 presents a summary of the recommendations, including weighted mean scores and consensus levels. Figure 2 highlights the highest-rated recommendations, showcasing key areas of strong stakeholder alignment. Detailed stakeholders’ perspectives and the underlying rationale for each recommendation is provided in Online Resource 2.

Table 2.

Consensus recommendations with their weighted mean score from the Nominal Group Technique on recommendations for regulatory convergence and streamlined biosimilar development

		Weighted mean scorea	Level of consensusb
General recommendations
A	We recommend educating all stakeholders. Increase educational initiatives to improve the understanding of the principles of biosimilarity and create confidence among all stakeholders including (clinical) regulators, industry professionals, healthcare providers, and patients	4.65	High
B	We recommend promoting convergence of regulatory requirements in guidelines for biosimilarity demonstration across jurisdictions based on scientific grounds	4.65	High
C	We recommend aligning regulatory requirements across jurisdictions building on the evolving advancements in analytical sciences, the accumulated knowledge gained through biosimilar evaluation and experience in clinical practice	4.60	High
D	We recommend facilitating proactive knowledge sharing among regulators on biosimilarity assessments. This includes in-depth, case-level exchange beyond general principles, such as sharing specific regulatory experiences and decision rationales from marketing authorizations	4.50	High
E	We recommend incorporating WHO revised biosimilar guidelines into national regulatory frameworks	4.30	High
F	We recommend relying on the biosimilarity assessments conducted by WHO Listed Authorities operating at maturity level 4, especially for regulators with limited resources. By doing so, they can utilize these assessments as a valuable point of reference, enabling efficient use of their limited resources	4.00	High
G	We recommend adopting a universally accepted template to enhance transparency in public assessment reports of biosimilar applications. This template should include clearly defined sections for different types of data (e.g., quality or clinical data) to ensure consistent and standardized documentation across regulatory agencies	4.00	High
H	We recommend developing International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines for biosimilar assessment, with the aim of fostering global harmonization	3.20	Low
Specific recommendations
Reference product
1	We recommend establishing harmonized and clear criteria in the national guidelines for the selection of the reference product. All relevant criteria that must be considered for the selection of a foreign-sourced reference product should be harmonized and clearly stated in the biosimilar guidelines from the respective national regulatory authority from which biosimilar approval is sought	4.55	High
2	We recommend considering mutual recognition of reference products among WHO-Listed Authorities operating at maturity level 4, supported by data-sharing agreements, to facilitate the acceptance of foreign-sourced reference products without requiring bridging studies	4.30	High
3	We recommend establishing a unified, international consensus on the criteria for the type and number of bridging studies required in biosimilar development	3.75	Moderate
4	We recommend adopting a gradual, stepwise approach to bridging studies, if these should be required. Begin with analytical bridging studies and proceed to pharmacokinetic bridging studies only if uncertainties or significant differences are identified in analytical bridging studies	3.90	Moderate
Analytical studies
5	We recommend providing education and training initiatives focusing on the selection of analytical methods. These should reflect the evolving nature of analytical sciences and understanding of quality data to ensure that regulators are equipped with the knowledge to apply the regulatory framework effectively	4.40	High
6	We recommend establishing “fit for purpose” criteria to ensure that the use of advanced analytical methods provide meaningful support in biosimilarity demonstration	4.10	High
Nonclinical evaluation: in vivo animal studies
7	We recommend establishing a unified, international consensus in biosimilar guidelines across regulatory agencies regarding the nonrequirement for in vivo animal studies	4.50	High
Clinical pharmacology (PK/PD) in healthy volunteers or patients
8	We recommend establishing an international, clear, and scientific consensus regarding the validity of a PD biomarker. PD biomarkers should only be required when they contribute to the understanding of the biological function and clinical performance of biosimilars	3.85	Moderate
9	We recommend providing incentives for biosimilar developers to encourage the development and use of PD biomarkers rather than making them a mandatory requirement to replace comparative clinical efficacy studies in patients	2.80	Low
Comparative clinical efficacy studies in patients
10	We recommend reconsidering the default requirement of comparative clinical efficacy studies for biosimilars if sufficient product knowledge, a satisfactory comparative analytical biosimilarity package (demonstrating structural and functional similarity) and a PK study providing safety and immunogenicity data are available	4.65	High
11	We recommend harmonizing guidelines on clinical trial designs for biosimilars of the same reference product across jurisdictions, including endpoint selection and sample sizes, to standardize the assessment methods and improve the predictability of the approval process	4.00	High
12	We recommend relying more on the use of pharmacovigilance systems to monitor the safety and efficacy of biosimilars following market entry, proportionally based on specified residual uncertainty. This can serve as an alternative to the pre-approval requirement of comparative clinical efficacy studies and/or as an additional assurance/confirmation for the biosimilarity demonstrated in analytical and PK/PD studies	3.60	Moderate
Local clinical studies
13	We recommend considering accepting clinical studies conducted for global submissions intended for all regions of the world instead of requiring local clinical studies for each biosimilar	4.50	High
14	We recommend assessing the necessity of local clinical studies based on available data and observed ethnic differences in the reference product, rather than mandating them for each biosimilar candidate by default	4.20	High

WHO World Health Organization, PK pharmacokinetic, PD pharmacodynamic

^aThe weighted mean score represents the average level of agreement among participants for each recommendation, rated on a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree)

^bThe level of consensus reflects the degree of agreement among participants for each recommendation. High consensus: recommendations with a weighted mean score of 4.0 or greater, with 80% or more of participants rating "agree" or "strongly agree. Moderate consensus: recommendations with a weighted mean score between 3.5 and 3.99. Low consensus: recommendations with a weighted mean score below 3.5

Fig. 2.

Schematic overview of the highest-consensus recommendations achieved among study participants for regulatory convergence and streamlining of biosimilar development

General Recommendations

The recommendations are listed from highest to lowest obtained consensus.

A. Enhancing stakeholder education to build experience and confidence in the safety, efficacy, and quality of biosimilars.

Participants stressed that mutual understanding of science-based biosimilarity principles are essential to facilitate convergence. For regulators, targeted training on the rigor and robustness of comparative analytical and human PK data was considered critical to achieving alignment in regulatory decision-making and enabling further tailoring of clinical requirements. For healthcare professionals, particularly those involved in advisory committees, guideline development, or reimbursement decision-making, education was viewed as necessary to strengthen confidence in the scientific basis of regulatory approvals and to support acceptance and prescribing of biosimilars, particularly in the contexts where tailored clinical data requirements are applied. This recommendation received the highest consensus. While this recommendation does not directly address technical issues on streamlining biosimilar development, it emerged during the focus group discussions as a system-level challenge. Participants highlighted that the success of streamlined biosimilar development depends in part on broader stakeholder trust and shared understanding of science-driven biosimilarity exercise.

B–C. Promoting regulatory convergence and aligning requirements based on current scientific evidence.

Participants noted that regulatory convergence is essential to streamline biosimilar development and approval to create a consistent and predictable regulatory pathway. While agreeing that each national regulatory authority should retain autonomy, participants highlighted the importance of alignment on only science-based requirements.

D. Facilitating in-depth knowledge sharing among regulatory agencies.

Proactive, in-depth knowledge sharing, including case-specific findings from marketing authorization applications (e.g., if a biosimilar candidate demonstrates higher immunogenicity than its RP), was highlighted as crucial for supporting resource-limited regions. The International Pharmaceutical Regulators Programme (IPRP), and its biosimilar working group, were particularly recognized for facilitating collaboration and information exchange among regulators.

E. Integrating 2022 WHO biosimilar guidelines into national regulatory frameworks.

A multi-organizational approach was strongly advocated for regulatory convergence, emphasizing the complementary roles of WHO and ICH. Participants acknowledged that while the WHO is not a regulatory authority, its revised 2022 biosimilar guideline provides a globally accepted scientific framework that supports harmonization efforts.

F. Reliance on WHO-Listed Authorities operating at maturity level 4 for biosimilarity assessments.

Several participants noted that scientific alignment already exists across stringent regulatory agencies (e.g., EMA, FDA), and that the key barrier to convergence is often the absence of formal reliance mechanisms. The concept of reliance was identified as a strategic opportunity for regulatory convergence by enabling resource-limited regulatory authorities to leverage biosimilar assessments by other trusted authorities, especially WHO Listed Authorities operating at maturity level 4 (i.e., advanced level of performance and continuous improvement), without compromising national sovereignty [23].

G. Adopting a universally accepted template for public assessment reports.

Participants recommended developing a universally adopted template to enhance transparency and consistent documentation in public assessment reports for biosimilars by including standardized sections for different types of data, such as quality and clinical data. The existing IPRP template, known as the Public Assessment Summary Information for Biosimilars, was referenced as a useful example [24].

H. Developing International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines for biosimilar assessment.

Developing separate ICH guidance for biosimilar assessment was suggested to facilitate regulatory convergence. However, industry stakeholders raised concerns since biosimilar assessment is already based on ICH Q5E guidance, and this could undermine the principle of biosimilars being comparable to their RPs. Some participants also noted that ICH’s process, while extensive, may be too slow and rigid for the rapidly evolving biosimilar landscape.

Specific Recommendations

The Reference Product

Recommendation 1: Harmonizing criteria for the selection of the reference product in biosimilar guidelines.

Participants noted challenges in procuring RPs for comparative testing, citing the high costs for clinical comparative efficacy studies that may not be scientifically justified, and practical barriers including limited market availability and originator companies’ reluctance to sell RP batches. A global comparator product was proposed to harmonize RP selection criteria. However, issues were highlighted about its implementation, including selecting the countries for sourcing and defining eligibility criteria.

Recommendation 2: Facilitating mutual recognition of reference products among WHO-Listed Authorities through data-sharing agreements.

Participants noted that despite some level of communication between regulatory authorities, developers may still need to obtain RP information themselves, such as manufacturing site details and specification variations. However, originator companies may be hesitant to disclose such details publicly. Therefore, participants recommended the establishment of data-sharing agreements, particularly between WHO-Listed Authorities operating at maturity level 4.

Recommendation 3: Establishing a unified, international consensus on the criteria for the type and number of bridging studies required in biosimilar development.

Many jurisdictions require analytical, and in some cases, clinical PK/PD bridging studies between locally sourced, foreign-sourced RP, and the biosimilar candidate. Participants highlighted inconsistencies in bridging studies requirements across regions and stressed the need for regulatory consensus on the type and number of required studies.

Recommendation 4: Establishing a stepwise approach to bridging studies in biosimilar development.

Since participants acknowledged that the cost of bridging studies is not trivial, duplicating these across multiple jurisdictions, adds substantially to the overall development costs. They suggested a stepwise approach, beginning with analytical bridging studies and advancing to PK bridging studies only if uncertainties are identified from the previous steps.

Analytical Studies

Recommendation 5: Implementing educational and training initiatives focusing on analytical studies.

Including compendial requirements for state-of-the-art and orthogonal analytical methods in biosimilar guidelines was discussed. While robust methods exist for evaluating critical quality attributes, participants agreed guidelines should focus on essential information. However, ensuring regulators have sufficient expertise to evaluate the analytical data package, was identified as a key challenge. Participants stressed the importance of education and training aligned with advancements in analytical methods.

Recommendation 6: Establishing “fit for purpose” criteria to ensure that the use of analytical methods contribute to meaningful support in biosimilarity demomynstration.

Participants discussed regulatory initiatives like the USFDA Research Roadmap for Biosimilars aiming to develop new analytical methods [25], and raised concerns regarding the overemphasis on increasingly sophisticated analytical methods. They suggested fit-for-purpose criteria to ensure that the choice of methods provide meaningful support for biosimilarity, rather than incremental improvements.

Nonclinical Evaluation: In Vivo Animal Studies

Recommendation 7: Establishing unified, international consensus regarding the non-requirement for in vivo animal studies

Some regions require in vivo animal studies, despite limited value and lack of scientific justification. Participants acknowledged the potential of validated animal models for specific purposes, such as assessing immunogenicity in complex biologics but stressed the need for regulatory consensus on minimizing in vivo animal studies to rare instances.

Clinical Pharmacology (PK/PD) in Healthy Volunteers or Patients

Recommendation 8: Establishing a scientific consensus on the validity of PD biomarkers.

Participants emphasized the early financial investments needed to identify and validate new PD biomarkers, along with challenges in analytical validation due to patient–patient variability and uncertainty in regulatory acceptability. They emphasized the need for regulatory consensus on the acceptability of new PD biomarkers.

Recommendation 9: Incentivizing the development and use of PD biomarkers.

Participants expressed concerns that regulators may consider PD biomarkers as a promising alternative to comparative clinical efficacy studies, emphasizing that expecting biosimilar developers, especially smaller companies, to invest in new PD biomarkers without success guarantee is rather optimistic. Consequently, the recommendation to incentivize PD biomarker development received the lowest consensus among all recommendations.

Comparative Clinical Efficacy Studies in Patients

Recommendation 10: Reconsidering the requirement of comparative clinical efficacy studies

Participants emphasized that comparative clinical efficacy studies often provide limited value in demonstrating biosimilarity, even for complex biologics such as mAbs and fusion proteins. They recommended scientifically justified criteria to determine their necessity and recognized exceptional cases where they may be warranted (e.g., when PK studies are not relevant, or additional therapeutic areas where more experience is needed). Furthermore, while the financial burden was noted as a contributing factor, particularly in cases where such studies are conducted despite limited scientific justification, this was framed within a broader concern regarding development inefficiencies that may impede development.

To reduce the reliance on comparative clinical efficacy studies when scientifically unjustified, participants suggested addressing the communication gap between varying disciplines among regulatory experts (e.g., those with quality and those with clinical expertise), who may lack a comprehensive understanding of the robustness of comparative analytical data. Implementing in-house training programs within regulatory agencies was recommended as a key strategy.

Recommendation 11: Harmonizing guidelines regarding clinical trial designs for biosimilars for the same reference product.

Participants highlighted varying regulatory requirements for clinical study designs and emphasized the need for standardized clinical trial designs for biosimilars of the same RP.

Recommendation 12: Relying more on the use of pharmacovigilance systems to monitor the safety and efficacy of biosimilars following market entry.

A few participants suggested relying more on pharmacovigilance systems to monitor biosimilar safety and efficacy in lieu of comparative clinical efficacy studies. This proposal received moderate consensus due to the importance of sufficient pre-approval evidence for biosimilarity and concerns about safety risks in regions with less robust pharmacovigilance systems.

Local Clinical Studies

Recommendations 13–14: Accepting clinical studies conducted for global submissions for biosimilar approval while evaluating the necessity of local clinical data based on observed ethnic differences with the reference product.

Participants noted that certain regulatory agencies, particularly in East Asia, require local clinical data for biosimilar approval. While ethnic sensitivity is typically addressed during the regulatory approval of the RP, participants recommended that local clinical studies should not be a default requirement for each biosimilar, emphasizing that the necessity for such data should be justified by observed ethnic differences with the RP. They acknowledged, however, that in jurisdictions where such requirements are legally mandated, legislative changes may be necessary to enable science-based regulatory decision-making.

Discussion

This study used modified NGT to identify and prioritize expert stakeholder perspectives on scientific and regulatory challenges associated with biosimilarity demonstration. In total, 22 recommendations were formulated, of which 16 achieved high consensus among regulators, academic researchers, and industry representatives with expertise in the development and/or regulatory approval of biosimilars and originator biologics.

Aligning Data Requirements for Biosimilar Development and Regulatory Approval Across Jurisdictions

The findings of this study highlight divergent regulatory requirements regarding RP selection criteria, in vivo animal studies, comparative clinical efficacy studies and local clinical studies. These divergences, which often stem from outdated legislation, are intended to maintain national sovereignty through independent decision-making, but often suffer from disparities in regulatory capacity, thereby hindering global regulatory convergence. As a result, global biosimilar developers must comply to the strictest requirements, necessitating additional studies that increase development costs and extend development timelines. Addressing these challenges requires not only technical alignment but, where relevant, changes to legislative frameworks to enable regulatory flexibility.

Recent updates in biosimilar guidelines in various jurisdictions demonstrate efforts to align regulatory standards with the current scientific understanding. The revised 2022 WHO biosimilar guidelines aim to reduce inconsistencies in regulatory requirements between regions, providing clarity on the acceptance of foreign-sourced RPs, promoting the 3Rs principle (replace, reduce, refine) to minimize in vivo animal studies, and reducing reliance on extensive clinical trials [26]. Similarly, the USFDA’s Modernization Act 2.0 (September 2022) eliminated mandatory animal testing, aligning with regulatory agencies such as EMA and UK MHRA [27]. Japan has also revised its biosimilar guidelines (January 2024), removing the requirement for local clinical data when ethnic factors are unlikely to affect outcomes [28]. Furthermore, a global comparator product has been proposed by Webster et al. in 2017, and, if implemented, would be a single version of the RP approved in a region or country that adopts ICH guidelines [29]. However, findings of this study emphasize the need for regulatory consensus and clarity on the sourcing of the comparator. These challenges underscore the urgent need for robust data-sharing agreements between (national) regulatory authorities.

Promoting Regulatory Convergence for Global Biosimilar Development Through Reliance

Participants emphasized the importance of aligning regulatory requirements with current scientific knowledge to create predictable and efficient biosimilar approval processes. This is particularly important for countries struggling with efficient regulatory evaluation of biosimilars owing to capacity or resource constraints [30]. In this context, findings from this study indicate that reliance models (e.g., work-sharing or unilateral recognition) are crucial, depending on the specific needs of regulatory authorities, to facilitate efficient use of (available) resources [31]. However, while several countries have adopted reliance, its practical implementation and impact on biosimilar approval remains unclear.

Several international initiatives illustrate the potential of reliance in promoting regulatory convergence. For example, ZAZIBONA, the ACCESS Consortium, and African Medicines Agency facilitate harmonization of regulatory standards for biosimilar evaluation, particularly in resource-constrained regions. Similarly, the IPRP supports aligning technical requirements and strengthening national regulatory frameworks for biosimilar evaluation [32]. WHO initiatives, including the prequalification procedure and the WHO-Listed Authorities framework, further demonstrate the benefits of reliance by promoting access to quality-assured biologics [33, 34]. Moreover, the WHO Collaborative Registration Procedure enables national regulatory authorities to accelerate registration of WHO-prequalified products, including biosimilars for trastuzumab and rituximab, by leveraging WHO’s prior assessments, thereby eliminating duplicative work.

The anticipated WHO implementation workshops, trainings, and case studies are essential for equipping regulatory authorities with the expertise needed to evaluate biosimilars, while also promoting the adoption of best practices [35]. These efforts should be tailored to the specific needs and maturity levels of regulatory authorities while avoiding a “one-size-fits-all” approach. The latter should be complemented with reliance mechanisms, such as leveraging biosimilar assessments by trusted regulatory authorities. This complementary approach creates a synergistic pathway to regulatory convergence, with reliance serving as a short-term solution to address immediate resource constraints, while WHO-led training and workshops lay the groundwork toward long-term reliance such as mutual recognition of biosimilar assessments on the basis of trust between regulatory authorities.

Reconsidering the Default Requirement for Comparative Clinical Efficacy Studies in Patients

Our findings highlight the importance of reconsidering the default requirement for comparative clinical efficacy studies, especially when robust analytical and human PK data are available. This aligns with growing evidence that questions the added value of comparative clinical efficacy studies in the biosimilarity exercise [11, 36–40]. For instance, a 2023 analysis of 36 biosimilar applications submitted to the EMA, indicated that in 67% of cases quality and clinical assessments were aligned, and that no applications were rejected solely on the basis of negative comparative clinical efficacy results, highlighting that robust quality and PK data were sufficient for regulatory approval [39]. Our findings emphasize the need for regulatory consensus on scientifically justified criteria for determining the necessity of these studies and reflected in updated guidelines. Specifically, alignment among advanced regulatory authorities such as EMA and USFDA is critical, as resource-limited regulatory authorities often rely on their regulatory standards.

Although economic considerations should not be the primary driver of regulatory reform, they may provide important context when supported by scientific rationale. For instance, only 7% of low-sales biologics have currently biosimilar candidates in development, potentially leading to €15 billion in missed savings in Europe by 2032 [16]. These figures highlight that tailoring clinical development of biosimilars, based on scientific rationale and evidence, could support future biosimilar development in underserved therapeutic areas.

Efforts to reduce reliance on comparative clinical efficacy studies are evident in the UK’s 2021 biosimilar guidelines, which advocate for case-by-case evaluations stating that “in most cases, a comparative efficacy trial may not be necessary if sound scientific rationale supports this approach” [41]. Similarly, the EMA issued a concept paper in November 2023, followed by a draft reflection paper in April 2025, to clarify the role of well-defined analytical and functional data in predicting clinical outcomes [42, 43]. In September 2023, the IPRP hosted a workshop exploring further the role of comparative clinical efficacy studies in the biosimilarity exercise [44]. The workshop’s insights will contribute to a risk-based framework outlining the conditions for waiving such studies [45]. In May 2025, the ICH announced a new multidisciplinary guideline “Framework for Determining Utility of Comparative Efficacy Studies in Biosimilar Development Programs” which, once finalized, will provide factors to consider when such studies are scientifically justified in biosimilar development [46]. The USFDA also published a Biosimilar User Fee Act (BsUFA) III research roadmap in early 2023 focusing on (i) improving analytical methods and (ii) reducing or replacing the need for clinical studies involving human subjects in biosimilar development [25].

It is interesting to note that incentivizing PD biomarker development received the lowest consensus, reflecting skepticism and disagreement between participants, in line with recent evidence [47]. Nonetheless, ongoing regulatory science initiatives continue to explore their potential role. For instance, the revised 2024 BsUFA III research roadmap (US) maintains PD biomarker development as a key research priority to reduce/replace comparative clinical efficacy studies, particularly for complex biologics [25]. The outcomes of this program, expected in 2027, will likely provide clarity and further inform the role and feasibility of PD biomarker development.

Enhancing Stakeholder Understanding and Trust in Biosimilars Through Targeted Education

The highest-rated recommendation from this study underscores the critical need for targeted education addressing different stakeholder groups. For regulators and policymakers, this involves fostering alignment and shared understanding of the robustness and predictive value of comparative analytical techniques, with the objective of supporting guideline revisions and further tailoring of clinical data requirements. For healthcare providers, education should address gaps in understanding of the scientific principles underpinning biosimilar development and regulatory approval [50–52], with a focus on the rigor and robustness of comparative analytical data in detecting the slightest differences in structural and functional parameters, which are critical for ensuring biosimilar quality, safety and efficacy. Strengthening this knowledge base is essential to build trust in the approval process and to encourage acceptance and prescribing of biosimilars.

As biosimilars expand into new therapeutic areas, ongoing education remains critical. This finding aligns with prior research highlighting education as a key driver for biosimilar acceptance and adoption [12, 13, 48, 49]. While significant progress has been made over the past two decades, such as dissemination of educational materials by regulatory authorities [53–55], our results emphasize the necessity for sustained, stakeholder-specific education. Education of healthcare professionals, and stakeholders more broadly, is essential to foster trust in biosimilars. An educational approach that demonstrates the scientific evidence behind regulatory decision-making will help ensure that this trust is built on a transparent, evidence-based foundation.

Strengths and Limitations

The NGT minimizes dominant voices and ensures equal contributions through structured grading. Purposeful sampling included stakeholders experienced in development and evaluation of biosimilars and/or originator biologics, enabling rich discussions. However, certain limitations exist. First, English-only participation may have excluded individuals with valuable insights due to language barriers. Second, the regional composition, primarily from Europe and North America, may have introduced geographical bias, potentially limiting the generalizability of the findings, particularly regulatory challenges unique to underrepresented regions. Future studies should broaden geographical representation to include stakeholders from Africa, South America, and Asia. Third, the high number (12 out 21) of industry stakeholders may have resulted in prioritization toward developer-focused recommendations, potentially limiting transferability to regulatory contexts. Lastly, while the virtual format enabled global participation, it may have limited the depth of discussions compared with in-person meetings.

Conclusions

This study proposes 16 concrete recommendations, which achieved high consensus to foster regulatory convergence and streamline biosimilar development. The highest-rated recommendations included enhanced stakeholder education including educational initiatives focused on analytical studies and addressing communication gaps between disciplines in regulatory assessors, promoting regulatory convergence and aligning data requirements with current scientific evidence, facilitating knowledge sharing, reconsidering the necessity of comparative clinical efficacy studies, harmonizing reference product selection criteria, eliminating in vivo animal studies, and accepting clinical studies conducted for global submissions. Overall, the findings underscore the importance of a science-based, risk-adapted regulatory framework that differentiates between scientifically justified requirements and those no longer aligned with current evidence or best practices. Addressing inefficiencies stemming from divergent regulatory requirements will be vital to support biosimilar development over the longer term. A globally streamlined biosimilar development and assessment will decrease development cost and timelines and thereby improve patient access to affordable biological medicines.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This work was supported by the KU Leuven and the Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL) Fund.

Declarations

Conflicts of interest

SS, IH, and AV are founders of the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL Fund). AV is involved in consulting, advisory work and speaking engagements for a few companies, i.e., Accord, Amgen, Biogen, Effik, Medicines for Europe, Pfizer/Hospira, Novartis, and Sandoz. SS was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD; he has participated in advisory board meetings for Pfizer, Organon and Amgen; he has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma, Pfizer and Biogen; and he has had speaking engagements for Abbott, Amgen, Biogen, Celltrion, and Sandoz. IS is an independent regulatory consultant with a long-standing background in biosimilars as an ex-affiliate to Sandoz. As such, she had speaking engagements for Sandoz in the past and served as the Chair of the Biosimilars Committee of IGBA. EC and LB have no conflicts of interest to declare. All authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Availability of data and materials

The datasets supporting the findings of this study are not publicly available due to the presence of sensitive information that could potentially identify participants and compromise their privacy. The data are, however, available from the authors upon reasonable request. For further information, please contact the corresponding author (a.vulto@erasmusmc.nl) .

Ethics approval

The study was approved by the Ethics Committee Research of UZ/KU Leuven (S67464). Written informed consent was obtained from all participants.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Code availability

Not applicable.

Author’s contributions

Study concept and design: all authors. Data collection: EC, SS, and AV. Data analysis: EC. Interpretation of data: all authors. Drafting of the manuscript: EC. Critical revision of the manuscript: all authors. All authors read and approved the final version of the manuscript.