Biosimilars and Interchangeability

Topic Information

Dear Colleagues,

Biological products include medications for treating many serious illnesses and chronic health conditions. A biosimilar is a biological product that is highly similar to, and has no clinically meaningful differences from, a biological product already approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA), which is also termed the reference product. All biological products are only approved after meeting both agencies’ rigorous approval standards. This definition is based on a comprehensive review of scientific evidence, which demonstrated that the biosimilar is highly similar to the reference product and that there are no clinically meaningful differences between the two products in terms of safety, purity, and potency (i.e., safety and efficacy). This evidence included comparisons of the products at an analytical level, using a comprehensive battery of chemical and biological tests and biological assays to confirm the similarities in the structural and functional characteristics of the two products (including those known to influence safety and efficacy).Additionally, it was supported by comparative data concerning human pharmacokinetics, clinical immunogenicity, safety, and overall effectiveness.

Nevertheless, an outstanding debate surrounds the question of whether biosimilars can be regarded as interchangeable with their reference biological products (and vice versa), or with biosimilars of the same reference product.

The EMA has not issued any official position or guidance on the interchangeability of biosimilars, as prescribing and advising physicians is the responsibility of each Member State of the European Union (EU). In Europe, a biosimilar that meets the rigorous regulatory requirements of the EU Biosimilar Approval Pathway may be considered interchangeable; however, it is at the discretion of each Member State to establish prescribing and dispensing protocols for the interchangeable use of biosimilars. In the United States, the regulatory assessment of biosimilar interchangeability differs from other approaches. The Biologics Price Competition and Innovation Act of 2009 (BPCIA) legally defines it, and biosimilars that are granted interchangeability status may be substituted for the reference biological product at the pharmacy level, subject to state laws, without the prescribing physician's intervention.

The development of biosimilar products may involve various facets, such as enhancing the recognition and evaluation of product attributes, defining acceptable differences in attributes more accurately between the reference product and the suggested biosimilar product, devising analytical methods to detect relevant disparities, and undertaking comparative analytical evaluation with advanced statistical methodologies. Additionally, exploring the use of in vitro and in silico methods to assess immunogenicity could potentially support demonstrating interchangeability between the reference product and the proposed interchangeable product. In this context, the “switching design” could be of interest.

We are pleased to invite all researchers and research teams that are interested in the field of biosimilars and interchangeability to contribute to this Topic with their manuscript(s). Full original research papers, short communications, and reviews regarding this topic are all welcome.

Dr. Alexis Oliva
Prof. Dr. Shein-Chung Chow
Dr. Joao Goncalves
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biologics biologics	-	-	2021	21.8 Days	CHF 1000
Molecules molecules	4.2	7.4	1996	15.1 Days	CHF 2700
Pharmaceuticals pharmaceuticals	4.3	6.1	2004	13.9 Days	CHF 2900
Pharmaceutics pharmaceutics	4.9	7.9	2009	15.5 Days	CHF 2900

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Published Papers (5 papers)

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Open AccessSystematic Review

Safety of Switching from a Reference Biologic to Its Biosimilar: A Systematic Review and Meta-Analysis

by Sarah Saad Aljahili, Samar Sami Alshuwairikh, Ahmed AlKhaldi, Abeer Althiban, Radwan Hafiz, Ghazwa B. Korayem and Hadeel Alkofide

Biologics 2025, 5(1), 6; https://doi.org/10.3390/biologics5010006 - 25 Feb 2025

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Abstract

Background: Biosimilars are designed to closely resemble their reference biologics in terms of quality, safety, and efficacy, with only minor variations in clinically inactive components and manufacturing methods. Evaluating the safety of switching between these products is critical for healthcare providers and patients. [...] Read more.

Background: Biosimilars are designed to closely resemble their reference biologics in terms of quality, safety, and efficacy, with only minor variations in clinically inactive components and manufacturing methods. Evaluating the safety of switching between these products is critical for healthcare providers and patients. Concerns may arise when transitioning patients from a reference biologic to a biosimilar or between different biosimilars. Objective: This systematic review and meta-analysis aims to evaluate the frequency of adverse events associated with switching from a reference biologic to its biosimilar, using data derived from randomized controlled trials (RCTs). Methods: A comprehensive search was conducted in MEDLINE and Cochrane Central databases from their inception to December 2024. Studies included RCTs that reported adverse reactions related to switching between reference-to-reference biologics and reference-to-biosimilar biologics. Record screening, data extraction, and risk of bias assessment were performed independently by two reviewers. Random effects models were applied to pool crude outcome data. Results: The search identified 668 abstracts, with an additional 14 studies found through hand-searching review articles. Of these, 12 trials involving 1326 participants in the reference–reference group and 1176 participants in the reference–biosimilar group met the inclusion criteria. The frequency of adverse events, serious adverse events, and treatment-related adverse events did not differ significantly between the reference–reference and reference–biosimilar groups: relative risk (RR) = 0.96 (95% confidence interval [CI], 0.85–1.08), RR = 1.06 (95% CI, 0.68–1.65), and RR = 1.03 (95% CI, 0.66–1.59), respectively. Heterogeneity was generally low to moderate across outcomes, and subgroup analyses based on disease type and reference product showed no differences. Conclusions: Switching between reference biologics and biosimilars demonstrates a comparable safety profile, suggesting that both options are viable. However, the findings are limited by the small number of trials and the scope of patient populations and products studied. PROSPERO registration number: CRD42021267205. Full article

(This article belongs to the Topic Biosimilars and Interchangeability)

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14 pages, 1361 KiB  

Open AccessArticle

Implementation of the Anchor-Based Indirect Comparison Method for Equivalence Margin Derivation in Biosimilar Development

by Claudia Hemmelmann, Rachid El Galta, Jessie Wang, Susanne Schmitt and Ramin Arani

Pharmaceuticals 2025, 18(3), 285; https://doi.org/10.3390/ph18030285 - 20 Feb 2025

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Abstract

Background/Objectives: To derive the equivalence margin (EQM), typically, a “classical” meta-analysis on direct within-trial estimation of the effect size of the reference drug compared to the placebo or standard of care is performed: a certain factor of the 95% confidence interval for [...] Read more.

Background/Objectives: To derive the equivalence margin (EQM), typically, a “classical” meta-analysis on direct within-trial estimation of the effect size of the reference drug compared to the placebo or standard of care is performed: a certain factor of the 95% confidence interval for the pooled treatment effect compared to placebo is used. However, treatment regimens in many indications are becoming more complex (e.g., combination treatments), and for most of these clinical study data, direct comparisons are not available. On the other hand, data for the comparison of the common treatment to the reference treatment in one study and to the placebo in another study are available in some situations. Methods: In such situations, an anchor-based indirect comparison can be applied to estimate the treatment effect of Reference vs. Placebo. This treatment effect (Reference vs. Placebo) can be estimated by calculating the difference of the two treatment effects and the variance as the sum of both variances. The 95% confidence interval of this estimated treatment effect can then be used to derive the EQM. To alleviate any concerns about the underlying assumptions of transitivity and consistency, multiple sensitivity analyses can be performed. Results: We present a case study for deriving the EQM using the anchor-based indirect comparison along with sensitivity analyses (i.e., direct comparison against similar reference drug, the impact of variation of treatment effect on Comparator, and effect size Reference vs. Placebo, including trial data with slightly different population characteristics) for a planned efficacy trial in the biosimilar setting. Conclusions: An anchor-based indirect comparison for EQM derivation is an approach health authorities can agree to if sufficiently supported through other means, e.g., relevant sensitivity analyses. Full article

(This article belongs to the Topic Biosimilars and Interchangeability)

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11 pages, 1137 KiB  

Open AccessArticle

The Role of Outcome Response Rate in Planning Biosimilar Studies Using Different Evaluation Metrics

by Liyi Cen, Ramin Arani and Dejun Tang

Pharmaceuticals 2025, 18(2), 243; https://doi.org/10.3390/ph18020243 - 12 Feb 2025

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Abstract

Background/Objectives: Biosimilar studies use overall response rate to assess clinical similarity. Sample size and power depend on the equivalence margin, defined in either risk difference or risk ratio scale. This manuscript investigates how different evaluation metrics and varying response rates affect study power. [...] Read more.

Background/Objectives: Biosimilar studies use overall response rate to assess clinical similarity. Sample size and power depend on the equivalence margin, defined in either risk difference or risk ratio scale. This manuscript investigates how different evaluation metrics and varying response rates affect study power. Methods: Two numerical simulations are conducted. The first is designed to test in the risk difference scale, while the second tests in the risk ratio scale. Both simulations consider no difference between the biosimilar and reference product. Response rates vary from 0.1 to 0.9, and all scenarios are repeated 10,000 times. Results: The study shows inconsistent results in testing the equivalence of overall response rate across the risk difference and risk ratio scales, even when the hypotheses are mathematically equivalent. Consequently, the study is often under powered for testing in both scales. Additionally, study power is sensitive to outcome response rate deviation, with different directions of change in the two different evaluation metrics. Conclusions: Biosimilar study design should avoid the concept of converting equivalence margins between risk difference and risk ratio scales, assuming no change in study power. Careful strategies should be planned for estimating overall response rates for sample size assessments. Full article

(This article belongs to the Topic Biosimilars and Interchangeability)

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13 pages, 772 KiB  

Open AccessArticle

Assessing Protein Content and Dimer Formation in the Bevacizumab Reference Product and Biosimilar Versions Marketed in Spain

by Alexis Oliva, Magdalena Echezarreta, Álvaro Santana-Mayor, Adrían Conde-Díaz, Joao Goncalves, Shein-Chung Chow and Matías Llabrés

Pharmaceutics 2024, 16(12), 1520; https://doi.org/10.3390/pharmaceutics16121520 - 26 Nov 2024

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Abstract

Background: The manufacture of biologics is a complex, controlled, and reproducible process that results in a product that meets specifications. This should be based on data from batches used to demonstrate manufacturing consistency. Ten batches of originator product (Avastin^®) were analyzed [...] Read more.

Background: The manufacture of biologics is a complex, controlled, and reproducible process that results in a product that meets specifications. This should be based on data from batches used to demonstrate manufacturing consistency. Ten batches of originator product (Avastin^®) were analyzed over a 10-year period. Methods: The β-expectation tolerance intervals and the process capability analysis were proposed to establish the specification limits for determining the acceptance criteria of the final product from the manufacturing process. Protein concentration and dimer content were utilized as CQAs. The analytical similarity between three biosimilars authorized in Spain since 2021 (Vegzelma^®, Alymsys^®, and Oyavas^®) and the originator product were evaluated for both CQAs using two methods: the quality range (QR) method, based on one sample per batch, and the QRML one, which takes into account the inter- and intra-batch variability of the originator product. Results: The results indicate that the two main sources of variation are under control; even the level of variability observed is close to the capability of the analytical method. The manufacturing process, therefore, continues under statistical control. Similarity is demonstrated for the bevacizumab concentration regardless of the approach used, whereas similarity is demonstrated for the dimer content for only one of the biosimilar products. Conclusions: The proposed methodologies allow for the analysis of the consistency of the manufacturing process and the variability from batch to batch. Full article

(This article belongs to the Topic Biosimilars and Interchangeability)

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Open AccessArticle

Characterization of Critical Quality Attributes of an Anti-PCSK9 Monoclonal Antibody

by Thayana A. Cruz, Nicholas R. Larson, Yangjie Wei, Natalia Subelzu, Yaqi Wu, Christian Schöneich, Leda R. Castilho and Charles Russell Middaugh

Biologics 2024, 4(3), 294-313; https://doi.org/10.3390/biologics4030019 - 11 Sep 2024

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Abstract

During early development of biopharmaceuticals, suboptimal producing clones and production conditions can result in limited quantities of high-purity products. Here we describe a systematic approach, which requires minimal amounts of protein (~10 mg) to assess critical quality attributes of a monoclonal antibody (mAb). [...] Read more.

During early development of biopharmaceuticals, suboptimal producing clones and production conditions can result in limited quantities of high-purity products. Here we describe a systematic approach, which requires minimal amounts of protein (~10 mg) to assess critical quality attributes of a monoclonal antibody (mAb). A commercial anti-PCSK9 IgG2 (evolocumab, Repatha^®) and an early-stage biosimilar candidate were compared head-to-head using a range of high-throughput physicochemical and in-vitro binding analytical methods. Overall, both mAbs were shown to be highly pure and primarily monomeric, to share an identical primary structure, and to have similar higher-order structural integrity, apparent solubility, aggregation propensity, and physical stability profiles under temperature and pH stress conditions. Low levels of dimers were detected for the innovator (1.2%) and the biosimilar candidate mAb (0.3%), which also presented fragments (1.2%). Regarding charge heterogeneity, the amount of the main charge isoform was 53.6% for the innovator and 61.6% for the biosimilar candidate mAb. Acidic species were 38% for the innovator and 30% for the biosimilar candidate. Variations in the relative content of a few N-glycan species were found. The in-vitro binding affinity to PCSK9 was monitored, and no differences were detected. The mathematical approach called “error spectral difference” (ESD), proposed herein, enabled a quantitative comparison of the biophysical datasets. The workflow used in the present work to characterize CQAs at early stages is helpful in supporting the development of biosimilar mAb candidates. Full article

(This article belongs to the Topic Biosimilars and Interchangeability)

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