Evaluating biosimilars: safety, efficacy, and regulatory considerations in clinical studies

Abstract

Biosimilars are a rapidly growing area of clinical research, yet they encounter significant challenges, especially in emerging markets where regulatory and clinical hurdles differ markedly from those in established regions like Europe and the US. This commentary addresses these unique challenges and offers new perspectives on the global adoption of biosimilars. It emphasizes the crucial role of real world evidence in supporting biosimilar approvals, an aspect often underrepresented in current literature. The commentary also provides a comparative analysis of the regulatory frameworks in China and Europe, highlighting how these differences shape biosimilar development and market approval processes. By focusing on the issues of indication extrapolation and immunogenicity, this commentary highlights the necessity of continuous real-world data collection to ensure the safety and efficacy of biosimilars across multiple indications. Our analysis enhances the understanding of biosimilar research and supports their broader adoption as safe, effective, and accessible healthcare solutions globally.

Introduction

Biosimilars are a rapidly expanding area of clinical research, yet they face substantial obstacles in real-world studies, particularly in emerging markets. This article highlights the regulatory and clinical challenges in these regions, emphasizing the underexplored role of real-world evidence (RWE) in biosimilar approvals. To ensure safety, rigorous evaluations of drug quality, clinical efficacy, and indication extrapolation are essential. Addressing these challenges will not only advance biosimilar research but also meet critical public health needs [1].

Biosimilar research and development

Standards and definitions for biosimilar research vary significantly between countries [2]. China’s regulatory pathway emphasizes comprehensive clinical trials, particularly for diverse patient populations. Conversely, Europe, guided by the European Medicines Agency (EMA), adopts a stepwise approach. The EMA’s guidelines mandate rigorous comparative studies with the reference product, focusing on quality, safety, and efficacy [3]. Since the EMA’s approval of the first biosimilar, Omnitrope® in 2006, Europe has approved 68 biosimilars by January 2022 [4]. These differences highlight the varying regulatory priorities influencing biosimilar development in China and Europe [5].

Clinical drug quality studies in real-world research on biosimilars

Drug quality research is crucial and complex in biosimilars’ clinical translation and development [6]. It supports the exploration of biosimilars, as studies show that data from clinical translation on drug quality are vital for understanding their clinical utility and determining their applicability in practice. A fundamental prerequisite is the similarity between a candidate biosimilar and the reference drug, directly related to drug quality [7]. Clinical trials can only proceed once a drug’s safety is confirmed through these studies. If trials show no significant differences between the biosimilar and the reference drug, the biosimilar’s pharmaceutical quality is considered satisfactory. The inherent microscopic heterogeneity of biological drugs, derived from organisms, tissues, cells, and bodily fluids, presents significant challenges. These drugs, characterized by large molecular weights and complex structures, require detailed quality analyses and enhanced research capabilities throughout biosimilar studies. Research must meet stringent drug research standards [8]. The study of pharmaceutical similarity between biosimilars and reference drugs is central. Typically, the same analytical methods should be used for head-to-head comparisons, adhering to a stepwise progression principle to facilitate evaluations. In clinical translation studies, assessing structural and functional differences between drugs is crucial. Comparison studies should focus on experimental comparisons of drug similarity to determine research efficacy and safety, including sensitivity and specificity tests [9].

Assessment and challenges of real-world clinical research on biosimilars

Research design

Biosimilar research demands high-quality design. Due to their long half-lives, biosimilars require carefully planned scientific responses and assessments. In addition, factors influencing treatment initiation and discontinuation need careful consideration in design and analysis. The potential for immunogenic reactions also limits the feasibility of specific research designs. For example, an immunogenic response in a crossover trial design can affect drug efficacy in subsequent studies. However, there are guidelines from regulatory bodies, and significant variations between biosimilars of the same reference drug require improved evaluations and discussions within the research design [10].

Study subjects and administration methods

In biosimilar research, the selection of the original reference drug is of paramount importance. Moreover, rigorous trial designs and selecting sensitive populations are crucial in real-world clinical interchange studies of biosimilars [11]. Short-term clinical endpoints help detect drug-related differences between patient groups. Drugs with severe adverse reactions should be excluded from administration methods, while others may be tested in healthy volunteers to confirm efficacy and safety. Although the Chinese “Clinical Medication of Biosimilars: An Evidence-Based Review and Protocol of Clinical Practice Guideline” [12] specifies administration methods and dosages, optimal dosages should be validated by varied dosing to ensure safe use.

Implications of immunogenicity assessments in biosimilar approval processes

Immunogenicity assessment

Immunogenicity remains a significant challenge in the approval and use of biosimilars. The development of anti-drug antibodies (ADAs) can not only reduce the efficacy of the biosimilar but also lead to adverse effects that were not observed with the reference product [13]. Recent advances in immunogenicity assessment techniques, such as the use of more sensitive assays for ADA detection and the integration of pharmacogenomics to predict patient susceptibility, have been instrumental in improving the safety profiles of biosimilars. However, the correlation between in vitro immunogenicity assays and clinical outcomes remains imperfect, highlighting the need for longitudinal studies that monitor ADA development and clinical efficacy over time. Moreover, regulatory guidelines now emphasize the importance of comparative immunogenicity studies not just before approval but throughout the lifecycle of the biosimilar, ensuring that any emerging safety signals can be promptly addressed.

Selection of efficacy endpoints

Selection of efficacy endpoints for biosimilars involves assessing therapeutic dosing regimens through endpoints such as progression-free survival (PFS) and overall survival (OS) [14]. Short-term efficacy endpoints such as total and complete pathological remission rates are used in comparative studies. The factors that determine these endpoints are critical to verifying the therapeutic efficacy of biosimilars, requiring a thorough assessment and summary of efficacy endpoints. At the same time, selecting efficacy endpoint indicators such as PFS, disease-free survival (DFS), and OS is crucial. These endpoints are essential because differences in monoclonal antibodies used in biosimilars can significantly impact drug performance. Carefully choosing and thoroughly studying these efficacy endpoints is critical to verifying the therapeutic efficacy of biosimilars, demonstrating the need to improve the focus on their selection and evaluation [15].

Elimination characteristics

The elimination characteristics of a drug are crucial in assessing the effectiveness of biosimilars. In biosimilar studies, parameters such as drug concentration, the area under the curve (AUC), and peak drug concentration are instrumental in differentiating drug use scenarios. The elimination characteristics of the biosimilar should align with those anticipated from predefined equivalency studies, with no adverse reactions observed during use. Typically, biosimilars have a longer half-life; any immunogenic reactions can influence these elimination characteristics. It is essential to thoroughly evaluate the elimination characteristics of biosimilars to ensure their effective use [16].

Clinical interchange study between biosimilar and reference drug

Safety, efficacy, and immunogenicity assessments between biosimilars and reference drugs do not significantly influence interchange therapy outcomes [17]. However, clinical complexity of patients with target diseases introduces potential for substantial confounding, the scope of clinical interchange studies on biosimilars remains limited, and these studies exhibit several inherent limitations. They tend to be unidirectional and show distinct differences in interchange processes between reference drugs and biosimilars. Existing studies generally indicate no significant differences in safety and efficacy after drug interchange, but research designs often need to be revised. Typical scenarios for single clinical drug interchange include switching from an original biologic to a biosimilar, from one biosimilar to another, or reverting to the original biologic. Small sample sizes, the absence of large-scale clinical trial analysis, and the lack of control groups constrain the applicability of the findings to broader clinical practice. Although efficacy assessments are performed after initial treatment in the conversion therapy process, the decision to continue interchange treatment often relies on safety and immunogenicity evaluations rather than efficacy alone. Given the limitations of current research [18], multiple clinical drug interchanges, defined as two or more switches between the original biologic and a biosimilar or between different biosimilars, are not recommended.

Path dependency in clinical interchange study evaluation

In the clinical application of biosimilars, reliance on single-product studies significantly streamlines research and design requirements and simplifies regulatory oversight [19]. However, this approach may depend on the established clinical interchange and evaluation pathway, which can neglect alternative research methodologies [20]. According to the WHO “Guidelines on Evaluation of Biosimilars” [21], initial phase results typically demonstrate minimal or no differences between the biosimilar candidate and the reference drug. When early clinical pharmacological comparisons predict clinical endpoint similarities, clinical similarity can be assessed based on these findings. the US Food and Drug Administration (FDA) “Considerations in Demonstrating Interchangeability with a Reference Product Guidance for Industry” suggests that the pharmacodynamic effects of the drug must be examined [22]. If the pharmacokinetic and pharmacodynamic outcomes are equivalent, further comparative clinical efficacy studies may not be necessary.

Indication extrapolation in real-world clinical interchange studies of biosimilars

EMA and FDA have established rigorous guidelines to mitigate the risks associated with the extrapolation of indications for biosimilars. These guidelines require a comprehensive evaluation of the biosimilar’s similarity to the reference product across multiple domains, including quality, safety, and efficacy. Specifically, the EMA’s stepwise approach includes detailed comparative analytical studies, non-clinical studies, and clinical studies that collectively provide robust evidence of biosimilarity. This systematic evaluation ensures that any extrapolation of indications is scientifically justified and supported by substantial data demonstrating that the biosimilar will perform similarly to the reference product in all approved indications.

To further mitigate risks, the EMA also emphasizes the importance of immunogenicity studies, particularly when extrapolating indications involving different therapeutic areas. Immunogenicity can vary between patient populations and disease states, and careful assessment is crucial to ensure that the biosimilar does not provoke an adverse immune response in new indications. By mandating these comprehensive assessments, the EMA and FDA reduce the likelihood of unexpected adverse outcomes when biosimilars are used in broader clinical contexts.

Extrapolating indications from biosimilars and aligning them with those of the reference drug requires further validation for application in multiple diseases [23]. Although this approach minimizes the need for additional clinical trials for drug developers, it introduces potential safety risks [24, 25]. New data have shown that the variability in receptor binding affinity and immunogenicity between different patient populations can result in disparate therapeutic outcomes, emphasizing the need for robust clinical evidence before broad indication extrapolation can be accepted [26]. Research on indication extrapolation must account for the diverse mechanisms of action associated with each indication, and ongoing post-marketing surveillance is crucial to ensure that biosimilars perform equivalently across all approved indication. Recent studies [27] also suggest that pharmacovigilance data should be systematically integrated into regulatory decision-making to assess the real-world performance of biosimilars across different patient cohorts.

In addition to pre-approval studies, continuous real-world data collection plays a critical role in supporting the safe and effective use of biosimilars across different indications [28]. Post-marketing surveillance and pharmacovigilance activities are essential to monitor the long-term safety and efficacy of biosimilars as they are used in diverse patient populations. RWE generated from these activities provides ongoing insights into the performance of biosimilars in clinical practice, allowing for the detection of any issues that were not apparent in pre-approval trials.

For example, real-world data can reveal variations in patient response due to factors such as comorbidities, concomitant medications, and genetic differences, which may not be fully captured in controlled clinical trials [29]. By integrating RWE into the regulatory framework, agencies like the EMA and FDA can continuously evaluate and refine their guidance on indication extrapolation, ensuring that biosimilars remain safe and effective throughout their lifecycle. This dynamic approach allows for adjustments based on emerging data, thereby enhancing patient safety and maintaining public confidence in biosimilar products.

Conclusion

This commentary highlights the unique challenges in emerging markets and the underrepresented role of RWE, offering crucial insights for advancing global biosimilar research. Ensuring the safety of biosimilars, particularly regarding interchangeability and indication extrapolation, remains paramount. Ethical concerns related to multiple switches and unstructured extrapolation in clinical studies require strong scientific support and vigilant post-market safety monitoring [30]. Overcoming regulatory and clinical barriers in emerging markets is essential for global biosimilar adoption [31]. Enhancing research on biosimilar substitutability and improving evaluations of safety practices are key steps toward safer and broader clinical use, contributing to more accessible and effective healthcare solutions.

Funding

This commentary was supported by Health Commission of Shanxi Province (2023109), and the Shanxi Province High-Quality Development of the Healthcare Industry Special Research Project (DJKZXKT2023206).

Conflicts of interest

Authors declare no conflicts of interest.