Biosimilars, the journey has begun

The expiry of the patent of several leading biological medicinal products has led to a surge in the development of 'biosimilar' products. However, in contrast to generic small-molecule medicines, biosimilars are not identical to their reference medicinal products. Full comparability in quality as well as in preclinical and clinical issues is required to register a biosimilar. The potential to induce antidrug antibodies after treatment with biological medicinal products is a safety issue that is an important consideration in the development of biosimilars and a critical aspect of regulatory filings. Regulatory authorities in the European Union require antidrug antibody responses to be evaluated and to be approached from a safety perspective: the higher the potential of immunogenicity to adversely affect a patient's health, the more diligently one should clarify the immunogenicity of the product. So far, however, no specific recommendations were given on a method for risk assessment or on the extent of the requisite antidrug antibody characterization. In this review, we will discuss the current state of knowledge on biosimilar products of infliximab, adalimumab and etanercept and present risk level-based schemes for the investigations of antidrug antibodies in non-clinical, clinical and pharmacovigilance studies.

ABSTRACTA biosimilar is a biological medicinal product that is comparable to a reference medicinal product in terms of quality, safety, and efficacy. SB4 was developed as a biosimilar to Enbrel® (etanercept) and was approved as Benepali®, the first biosimilar of etanercept licensed in the European Union (EU). The quality assessment of SB4 was performed in accordance with the ICH comparability guideline and the biosimilar guidelines of the European Medicines Agency and Food and Drug Administration. Extensive structural, physicochemical, and biological testing was performed with state-of-the-art technologies during a side-by-side comparison of the products. Similarity of critical quality attributes (CQAs) was evaluated on the basis of tolerance intervals established from quality data obtained from more than 60 lots of EU-sourced and US-sourced etanercept. Additional quality assessment was focused on a detailed investigation of immunogenicity-related quality attributes, including hydrophobic variants, high-molecular-weight (HMW) species, N-glycolylneuraminic acid (NGNA), and α-1,3-galactose. This comprehensive characterization study demonstrated that SB4 is highly similar to the reference product, Enbrel®, in structural, physicochemical, and biological quality attributes. In addition, the levels of potential immunogenicity-related quality attributes of SB4 such as hydrophobic variants, HMW aggregates, and α-1,3-galactose were less than those of the reference product.

The concept of similar biological medicinal products (‘biosimilar’ medicinal products) allows pharmaceutical companies to develop products based on an abridged dossier once the marketing protection of the ‘reference’ biological medicinal product has expired. A biosimilar medicinal product can be granted a marketing authorization provided that its similarity to a reference product is established in terms of quality, safety and efficacy (step-wise comparability exercise). A decision to launch a biosimilar medicinal product on the market is taken if it has a similar efficacy and comparable or better (less) immunogenicity than the chosen reference biological medicinal product. However, this decision is based on limited data and the comparability program may detect substantial differences in immunogenicity profiles but is likely incapable of detecting rare events. This is why clinical experience, through clinical trials and extensive pharmacovigilance programs, remains the most reliable way to assess the immunogenicity and tolerance profile of recombinant therapeutic proteins. Substitution of one biological medicinal product by a biosimilar medicinal product is not currently recommended before long-term clinical efficacy and safety have been acquired in all relevant populations. Here we review recent regulatory guidelines provided by EMEA and comment on the marketing authorizations and risk management plans of two recently approved biosimilar somatropins.

European Pharmacopoeia Activities on Control of Nitrosamines and other DNA-Reactive Impurities

The regulatory framework for biosimilars was established across Europe in 2005 based on the concept of biosimilarity. This legislation secures the manufacturing, evaluation, and market authorization (MA) of high-quality safe and efficacious biopharmaceuticals that are highly similar to their reference medicinal product (biosimilars). Demonstration of biosimilarity is documented by full-scale comparability exercises between the biosimilar and the reference product at quality, preclinical, and clinical level. However, the complexity, diversity, and heterogeneity of biosimilars, both in structure and manufacturing, combined with the scientific knowledge accumulated in biotechnological analysis of recombinant therapeutic proteins requires continuous improvement of the regulatory framework based on the evolution and experience gained in this field. This current opinion article presents the concept of biosimilarity, discusses the extrapolation of indications that is acceptable based on a case-by-case basis by CHMP/EMA and uncovers other challenges lying ahead in the development of biosimilars. Biosimilars are still quite 'young' products that require worldwide attention.

Human IgG2 subclass antibodies exhibit complex interchain disulfide bonding patterns, resulting in three conformational structures: IgG2-A, IgG2-A/B and IgG2-B. The structural patterns of IgG2 disulfide isoforms fundamentally influence a spectrum of critical attributes, from molecular properties such as surface charge distribution, hydrophobicity, and N-glycosylation to ultimate biological activity and potency. Evenity (romosozumab) is a humanized IgG2 monoclonal antibody targeting sclerostin, for the treatment of osteoporosis. During the development of a romosozumab biosimilar, difference in the disulfide isoform profiles of the biosimilar and the reference medicinal product (RMP) was identified. Compared with RMP, the biosimilar presented a reduced IgG2-B content, accompanied by elevated IgG2-A/B and IgG2-A contents. The disulfide isoforms were fractionated via CEX-HPLC or enriched via a redox procedure, after which the key physicochemical properties, binding ability and potency were investigated. The analytical data revealed that, despite observed differences in specific physicochemical properties-including surface charge distribution, hydrophobicity, and high mannose content-the biosimilar's disulfide isoforms exhibited comparable potency to the RMP. These findings suggest that the observed disulfide isoform profile differences do not compromise the potency of romosozumab under the conditions tested.

Objective: To compare the antitumor efficacy, safety, and pharmacodynamic (PD) characteristics of Hetero-rituximab (test) with reference medicinal product (rituximab, Roche) in non-Hodgkin's lymphoma. Patients and Methods: One hundred and thirty-five patients with diffuse large B-cell lymphoma (DLBCL) were randomized to receive intravenous infusion of either test or reference product. Efficacy (best overall response [BOR] rate [primary end point]), safety, PD (CD19), and immunological assessments (secondary end points) were done at the end of cycle 3 and cycle 6. Results:: At the end of 6 cycles, BOR rate was 73.47% in Hetero-rituximab test arm compared to the 69.09% in reference arm. Anti-rituximab antibodies were found to be negative at cycle 3 and cycle 6 for all patients. Patients treated with Hetero-rituximab show a significant depletion in CD19+ cell which was comparable with reference drug. Safety and immunogenic potential of the test drug was comparable to the reference drug in the patients of DLBCL. Conclusion: BOR rate at cycle 3, cycle 6, and end of the study lies within the prespecified limit for noninferiority which concludes that test product is therapeutically noninferior to reference medicinal product.

ABSTRACTCT-P10 (Truxima™) was recently approved as the world's first rituximab biosimilar product in the European Union (EU) and South Korea. To demonstrate biosimilarity of CT-P10 with the reference medicinal product (RMP), extensive 3-way similarity assessment has been conducted between CT-P10, EU-Rituximab and US-Rituximab, focusing on the physicochemical and biological quality attributes. A multitude of state-of-the-art analyses revealed that CT-P10 has identical primary and higher order structures compared to the original product. Purity/impurity profiles of CT-P10 measured by the levels of aggregates, fragments, non-glycosylated form and process-related impurities were also found to be comparable with those of RMPs. In terms of the post-translational modification, CT-P10 contains slightly less N-terminal pyro-glutamate variant, which has been known not to affect product efficacy or safety. Oligosaccharide profiling has revealed that, although CT-P10 contains the same conserved glycan species and relative proportion with the RMPs, the content of total afucosylated glycan in CT-P10 was slightly higher than in EU- or US-Rituximab. Nevertheless, the effect of the observed level of afucosylation in CT-P10 drug product on Fc receptor binding affinity or antibody-dependent cell-mediated cytotoxicity was found to be negligible based on the spiking study with highly afucosylated sample. Arrays of biological assays representative of known and putative mechanisms of action for rituximab have shown that biological activities of CT-P10 are within the quality range of RMPs. Recent results of clinical studies have further confirmed that the CT-P10 exhibits equivalent clinical efficacy and safety profiles compared to EU- and US-Rituximab. The current 3-way similarity assessment together with clinical study results confidently demonstrate that CT-P10 is highly similar with EU- and US-Rituximab in terms of physicochemical properties, biological activities, efficacy, and safety for its final approval as a biosimilar product.

Problem setting. The approximation of Ukrainian legislation to the European Union (EU) legislative framework allows for the improvement of systems for the production of innovative medicinal products, particularly advanced therapy medicinal products (ATMP). This, in turn, requires a properly updated legislative framework that must meet EU standards. The adoption of the guideline of the Ministry of Health of Ukraine 42-4.0:2020 marked a new stage in the regulation of the production practice of ATMP in Ukraine. However, the effectiveness of implementing the provisions of this Ukrainian guideline directly depends on the level of consistency of the domestic standards of ATMP manufacturing practice with the standards of the European Union. That is why analysis is necessary to be carried out to define the current state of the Ukrainian system of legal regulation in the field of manufacturing practice of ATMP. Analysis of recent researches and publications. The general characteristics of legal regulation of public relations, which are formed in the manufacturing practice of medicinal products, became the subject of consideration by such researchers as O. G. Alekseev, O. Ya. Andriichuk, S.V. Vasiliev, V. M. Pashkova and others. However, in modern legal literature, issues related to the manufacturing practice of ATMP for human use were not raised. The target of the research is to analyse of Ukrainian and EU legislation regulating the manufacturing practice of ATMP. A rticle’s main body. The regulation of ATMP production within the framework of the European legislative process was directly related to all four categories of the latter, which was finally defined and fixed by the adoption of Regulation 1394/2007/EC of the European Parliament and of the Council, which entered into force on December 30, 2008. Since that time, active work had begun on the introduction of a new category of biological medicinal products (such as ATMP) to Volume 4 of EudraLex, which ended with the implementation on January 31, 2013, of the amended Appendix 2 of Volume 4 of EudraLex, which contained, along with the general rules for implementing good manufacturing practices of medicinal products as well as special regulations related to the manufacturing of ATMP. Subsequently, in connection with the update of manufacturing practice standards and as a result of the adoption of the guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (European guideline on GMP for ATMP) in 2018, the provisions of Annex 2 Therefore 4 of EudraLex were changed and no longer applied on ATMP. Following the development of the legal definition of ATMP in Ukrainian legislation, we should note that in the guideline of the Ministry of Health of Ukraine 42-4.0:2013, in contrast to the previous editions, such a category of medicinal products as «high-technology (biotechnological) medicinal products» was used for the first time. The Ukrainian implementation of the European guideline on GMP for ATMP was carried out in 2020. The guideline of the Ministry of Health of Ukraine 42-4.0:2020 was created with a separate guideline 42-4.9:2020 as a part of it. The ATMP was used instead of «high-technology (biotechnological) medicinal products» in the guideline 42-4.9:2020. Conclusions and prospects for the development. During the development of the legal definition of ATMP in Ukrainian legislation, the term was changed from «high-tech (biotechnological) medicinal products» to «advanced therapy medicinal products». The manufacturing practice of the ATMP was first regulated by the guideline of the Ministry of Health of Ukraine 42-4.0:2013, which was based on Appendix 2 Volume 4 of EudraLex in 2013. Then, due to the adoption of the European guideline on GMP for ATMP in 2018, the next Ukrainian guideline was created in Ukraine, namely 42-4.9:2020 as part of the guideline of the Ministry of Health of Ukraine 42-4.0:2020. The guideline 42-4.9:2020 for the first time introduced combined ATMPs as a separate subgroup of ATMP, provided separate measures for the production of combined ATMPs, and also indicated an exhaustive list of all other types of ATMPs that comply with the provisions of Regulation 1394/2007/EC of the European Parliament and of the Council. Although the domestic guidelines are properly harmonized with European standards of ATMP manufacturing, there is a need to adopt auxiliary normative acts designed to implement certain provisions of the guideline of the Ministry of Health of Ukraine 42-4.0:2020.

The presented article provides a systematic review of the pharmaceutical legislation (EU Pharmaceutical Package) – the current proposal of the European Commission for a new Directive, repealing and replacing Directives and modifying Regulations of the European Parliament and of the Council, incorporating the relevant parts of the Regulation concerning medicinal products for pediatrics, Regulation for orphan drugs and others, aiming at revision of the pharmaceutical legislation in the context of antimicrobial resistance and challenges facing the introduction of innovative antimicrobial medicines in Europe. It outlines a critical analysis on the impact of the changes in the context of introduction of innovative antimicrobial medicinal products with an emphasis on unsatisfied medical demands of the European population. The revision of the pharmaceutical legislation provides an argument to consider that the proposed Pharmaceutical Package could resolve some of the issues associated with the access to novel antibiotic medicines. It is necessary to find a consensus and a balance between, on the one hand, meeting the need for antibiotics for the citizens of the European Union and, on the other hand, providing timely access to generic medicines to meet the needs of the population.

This article provides an overview of the current situation regarding the traceability of medicinal products, with a focus on drug safety and biologics. Limited traceability of biologics, in particular with regard to the batch number, is associated with incomplete recording of exposure information in clinical practice. The current pharmaceutical barcode standards in the EU do not support the automatic recording of dynamic product information, such as batch numbers and expiry dates, by means of electronic barcode scanning in clinical practice. New barcode requirements, such as the 2D DataMatrix with encoded batch numbers and expiry dates, provided on both the primary and the secondary package, can facilitate routine barcode scanning at all points in the supply chain in different healthcare settings. To build a full track-and-trace system for medicines with electronic capture of relevant exposure information, alignment with other topics, such as the Falsified Medicines Directive and initiatives to reduce medication errors, is needed to increase the buy-in from all stakeholders and to solve multiple issues with a joint effort.

Biosimilars: what clinicians should know

In this dissertation, the difficulties and challenges related to the approval of anticancer medicinal products are discussed. In Chapter 1, a general introduction is provided, which focusses on the shift towards precision medicine, the European Union legal framework, authorised anticancer medicinal products and the relevance of evidence generation. In Chapter 2, an overview on European Commission (EC) designated orphan medicinal products (OMPs) for the treatment of pancreatic cancer is provided. We conclude that the success rate of OMPs for pancreatic cancer that reach the market is low. Increasing this rate is something to aspire. Developers are advised to make optimal use of orphan incentives. In addition, developers are strongly encouraged to provide yearly updates on advancements in development. Chapter 3 is dedicated to the question if investigational medicinal products that were granted Breakthrough Therapy designation (BTD) by the Food and Drug Administration (FDA) are truly breakthroughs. Based on our findings, we conclude that the success rate of the BTD program is lower than anticipated, given the few clinical trials that were assigned a high ESMO-MCBS score. Nonetheless, we believe that programs for fast drug approval do have a place in current regulatory practices. Chapter 4 provides detail on how clinical benefit of anticancer medicinal products tested in single-arm trials (SATs) was determined. Our research indicates that there is some room for improvement. This includes prespecifying and motivating a clinically relevant effect size and aligning the sample size to that effect. External controls may facilitate in the contextualisation process, but the limitations associated with such indirect comparisons must be addressed. We consider it of value to further discuss among stakeholders when approval on the basis of lower levels of evidence is justified. In Chapter 5, the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product on the basis of results from investigator-initiated trials (IIT) are explored. We conclude that it is possible to support an extension of indication of an authorised medicinal product on the basis of results from IITs, but regulatory requirements still need to be met. Therefore, a collaborative approach and early dialogue between stakeholders is of importance for future decision-making. In Chapter 6, decision-making aspects of the first tissue-agnostic approvals are compared between the European Medicines Agency (EMA), FDA and Pharmaceuticals and Medical Devices Agency (PMDA). Post-marketing measures related to the tissue-agnostic indication were of specific interest. Our results show that there are different approaches to further confirm the tissue-agnostic indication in the post-marketing setting, albeit these are not without inherent limitations. For future applications, a global strategy toward data generation post-marketing may be of interest. The final chapter (Chapter 7) provides a general discussion and perspectives for follow-up research. It is concluded that further research is needed to ensure that beneficial medicinal products are timely authorised, especially when they address an unmet medical need. Reflecting on prior decision-making and exploring regulatory possibilities, from a multi-stakeholder perspective, will be necessary to continue safeguarding public health.

Because the falsification of medicines is a global problem, requires increased and effective international coordination and cooperation to ensure the effectiveness of the strategies to combat counterfeiting, especially in relation to the sale of such products on the Internet. In the context of people’s health and life rank foremost among the values and interests protected by the TFEU, this article examines the evolution of the legislative process regulating the internal market for medicinal products in order to ensure a high level of protection of public health against falsified medicines and to present the legislative initiatives that have been taken at EU level taking account of new risk profiles, measures meant to ensure, at the same time, the functioning of the internal market of medicinal products. However, this article aims to address consumers’ right to have access to safe, effective, quality and innovative medicinal products as a right of the European patient. Ensuring the free movement of medicinal products on the EU market must not violate or restrict this fundamental right of thepatient.The threat that falsified medicines pose to public health is also recognized by the World Health Organization (WHO), which has established the International Medical Products Anti-Counterfeiting Taskforce ("IMPACT").IMPACT has developed the Principles and Elements for National Legislation against Counterfeit Medical Products, which were endorsed by the IMPACT General Meeting in Lisbon on 12 December 2007.

Because the falsification of medicines is a global problem, requires increased and effective international coordination and cooperation to ensure the effectiveness of the strategies to combat counterfeiting, especially in relation to the sale of such products on the Internet. In the context of people’s health and life rank foremost among the values and interests protected by the TFEU, this article examines the evolution of the legislative process regulating the internal market for medicinal products in order to ensure a high level of protection of public health against falsified medicines and to present the legislative initiatives that have been taken at EU level taking account of new risk profiles, measures meant to ensure, at the same time, the functioning of the internal market of medicinal products. However, this article aims to address consumers’ right to have access to safe, effective, quality and innovative medicinal products as a right of the European patient. Ensuring the free movement of medicinal products on the EU market must not violate or restrict this fundamental right of thepatient.The threat that falsified medicines pose to public health is also recognized by the World Health Organization (WHO), which has established the International Medical Products Anti-Counterfeiting Taskforce ("IMPACT").IMPACT has developed the Principles and Elements for National Legislation against Counterfeit Medical Products, which were endorsed by the IMPACT General Meeting in Lisbon on 12 December 2007.