Similar Biological Medicinal Products Research Articles

Current status, issue and future perspectives for biosimilars in Japan from the viewpoint of cost-effectiveness

Abstract In Japan, maintaining the universal health insurance system has become a major social issue in our rapidly aging society with soaring expense of social security contributions and skyrocketing medical costs, etc. Nowadays generic medicines have become standard therapeutic medicines even in the field of cancer treatment. In terms of cost-effectiveness, biosimilars are expected to enhance patients’ access to beneficial treatment and so contribute to patients’ quality of life as well as reducing the economic burden and total medical expenses while providing equivalent therapeutic outcomes inexpensively compared to the original biologics. Regarding the approval requirements of biosimilars, unlike generic products, they need a Phase III clinical trial in addition to the characterization study which proves similarity to the originals. Biosimilars have been approved through a review process of an application package which is similar to that of new drugs. However, in Japan, biosimilars have not become standard therapeutic choices yet. Approvals of biosimilars and their prevalence in the medical front have been proceeding in Europe and those products have grown in popularity as standard therapeutic choices. In European countries, the European Medicines Agency, academic societies and governmental authorities in each country have implemented a variety of measures to facilitate use of biosimilars. As part of such efforts, the EMA published a guideline on similar biological medicinal products containing G-CSF in 2006. In overseas ASCO and ESMO have already issued a position paper and statement on biosimilar products. In Japan, the Japan Society of Clinical Oncology recommends the biosimilars in its guideline for acceptable use in 2013. This presentation covers the initiatives for biosimilars in Europe and the US, the situation and the challenges in Japan as well as the activities of the Japan Biosimilar Association.

From bioequivalence to biosimilars: How much do regulators dare?

The main advantage of an abbreviated licensing pathway is the possibility of extrapolating efficacy and safety data from an original medicinal product to a subsequent "copy" version, thereby reducing the clinical development programme in particular. For small-molecule chemically synthesized generics, such an abbreviated licensing pathway was established decades ago, whereas it was only more recently implemented for similar biological medicinal products, so-called biosimilars. Clinicians and patients have repeatedly expressed concerns about the efficacy and safety of biosimilars, especially in 'extrapolated' indications for which no own clinical data have been generated. Generic drugs usually contain well-defined active ingredients whose "identity" with that of the originator, the so-called reference product, is easily verifiable. Biological substances are generally more complex and difficult to characterize. They are produced in living organisms and therefore naturally exhibit some intrinsic variability, i.e. microheterogeneity. Since the chosen expression system and the manufacturing conditions influence the quality characteristics of a biological substance, mostly its posttranslational modifications such as the glycosylation pattern, it is unlikely that two independent manufacturing processes can achieve completely identical biologicals. A biosimilar, especially if it is a glycoprotein, can therefore, at best, be highly similar to the reference product. It seems that the not-identical-but-(highly)-similar-paradigm for biosimilars is often not well understood and causes confusion. However, while at first glance an abridged approval pathway for biosimilars appears to be daring, it is in fact based on sound scientific reasoning. A biosimilar applicant has to provide a considerably larger package of comparative data than a generic applicant to ensure that the biosimilar can indeed rely, for the purpose of licensing, on the efficacy and safety experience gained with the reference product. While for a generic, the demonstration of similar in vitro dissolution and in vivo bioavailability (so-called 'bioequivalence') is sufficient to conclude therapeutic equivalence with the reference product, for a biosimilar, comparable physicochemical, biological and functional characteristics as well as efficacy and safety/immunogenicity with the reference product must be demonstrated. In addition, unlike generics, any extrapolation to other indications of the reference product must be scientifically justified. More than 10 years of successful clinical experience with biosimilars in the EU support the credibility of the scientific principles guiding the biosimilar concept. So far, there has been no need for either withdrawal of an approved biosimilar or for additional labelling because of efficacy or safety concerns.

Epoetin Biosimilars in the Treatment of Chemotherapy-Induced Anemia: 10Years' Experience Gained.

High-quality, safe, and effective biosimilars have the potential to increase access to biological therapies worldwide and to reduce cancer care costs. The European Medicines Agency (EMA) was the first regulatory authority to establish legislative procedures for the approval of biosimilars when they published their guidelines on similar biological medicinal products in 2005. Biosimilar epoetins were first approved in 2007, and a wealth of data has been collected over the last decade. Two biosimilar epoetins (under five commercial names) have been approved by the EMA so far. The availability of epoetin biosimilars generated discussion among the oncology community regarding prescribing these products, their efficacy, and their safety. These agents are approved only if they are shown in extensive analytical and clinical testing to have comparable quality, safety, and efficacy to the reference medicine, and real-world studies provide further data that biosimilar epoetins are an effective and well-tolerated option for the treatment of chemotherapy-induced anemia in patients with cancer. Other countries have adopted similar regulatory pathways to those in Europe and have approved epoetin biosimilars. The now extensive European experience with biosimilar epoetins should reassure regulators from other territories.

Interchangeability of Biosimilars: A European Perspective

Many of the best-selling 'blockbuster' biological medicinal products are, or will soon be, facing competition from similar biological medicinal products (biosimilars) in the EU. Biosimilarity is based on the comparability concept, which has been used successfully for several decades to ensure close similarity of a biological product before and after a manufacturing change. Over the last 10 years, experience with biosimilars has shown that even complex biotechnology-derived proteins can be copied successfully. Most best-selling biologicals are used for chronic treatment. This has triggered intensive discussion on the interchangeability of a biosimilar with its reference product, with the main concern being immunogenicity. We explore the theoretical basis of the presumed risks of switching between a biosimilar and its reference product and the available data on switches. Our conclusion is that a switch between comparable versions of the same active substance approved in accordance with EU legislation is not expected to trigger or enhance immunogenicity. On the basis of current knowledge, it is unlikely and very difficult to substantiate that two products, comparable on a population level, would have different safety or efficacy in individual patients upon a switch. Our conclusion is that biosimilars licensed in the EU are interchangeable.

Meeting the Rigorous Demands of Biosimilar Pharmacokinetics

International Journal of PharmacokineticsVol. 2, No. 1 EditorialMeeting the rigorous demands of biosimilar pharmacokineticsSaara Mansouri, Jennifer Zemo & Krystal J AlligoodSaara Mansouri BioAgilytix Labs. 2300 Englert Drive, Durham, NC 27713, USASearch for more papers by this author, Jennifer Zemo BioAgilytix Labs. 2300 Englert Drive, Durham, NC 27713, USASearch for more papers by this author & Krystal J Alligood*Author for correspondence: E-mail Address: Krystal.Alligood@bioagilytix.com BioAgilytix Labs. 2300 Englert Drive, Durham, NC 27713, USASearch for more papers by this authorPublished Online:19 Jan 2017https://doi.org/10.4155/ipk-2016-0024AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: bioanalytical method validationbiosimilarligand-binding assayoriginatorpharmacokineticsReferences1 Cai XY, Gouty D, Baughman S, Ramakrishnan MS, Cullen C. Recommendations and requirements for the design of bioanalytical testing used in comparability studies for biosimilar drug development. Bioanalysis 3(5), 535–540 (2011).Link, CAS, Google Scholar2 DeSilva B, Smith W, Weiner R et al. Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm. Res. 20(11), 1885–1900 (2003).Crossref, CAS, Google Scholar3 Marini JC, Anderson M, Cai XY et al. Systematic verification of bioanalytical similarity between a biosimilar and a reference biotherapeutic: committee recommendations for the development and validation of a single ligand-binding assay to support pharmacokinetic assessments. AAPS J. 16(6), 1149–1158 (2014).Crossref, CAS, Google Scholar4 Colbert A, Umble-Romero A, Prokop S et al. Bioanalytical strategy used in development of pharmacokinetic (PK) methods that support biosimilar programs. MAbs 6(5), 1178–1189 (2014).Crossref, Google Scholar5 Xiao YQ, Halford A, Hayes R. Bioanalytical method development and validation of biosimilars: lessons learned. MOJ Immunol. 1(1), 1–4 (2014).Crossref, Google Scholar6 European Medicines Agency. EMEA/CHMP/BWP/49348/2005. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (2006). www.federalregister.gov/documents/2010/10/05/2010-24853/approval-pathway-for-biosimilar-and-interchangeable-biological-products-public-hearing-request-for.Google Scholar7 US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). Quality considerations in demonstrating biosimilarity to a reference protein product (2012) (Draft). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf.Google Scholar8 US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). Scientific considerations in demonstrating biosimilarity to a reference product (2012) (Draft). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf.Google Scholar9 European Medicines Agency. EMEA/CHMP/EWP/192217/2009. Guideline on bioanalytical method validation (2012). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf.Google Scholar10 US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Drug Evaluation and Research (CDER). Bioanalytical Method Validation (2013) (Draft). www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm368107.Google Scholar11 US Department of Health and Human Services. Food and Drug Administration. Docket No. FDA-2010-N-0477. Approval pathway for biosimilar and interchangeable biological Products. Public Hearing (2010). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf.Google Scholar12 European Medicines Agency. CHMP/437/04. Guideline on similar biological medicinal products (2015). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf.Google Scholar13 European Medicines Agency. EMEA/CHMP/BMWP/42832/2005. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (2015). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf.Google ScholarFiguresReferencesRelatedDetails Vol. 2, No. 1 Follow us on social media for the latest updates Metrics Downloaded 69 times History Published online 19 January 2017 Published in print January 2017 Information© Future Science LtdKeywordsbioanalytical method validationbiosimilarligand-binding assayoriginatorpharmacokineticsFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

PHP62 - Assessment Of Regional Legislation Related To The Use Of Similar Biological Medicinal Products: The Italian Case Study

PHP62 - Assessment Of Regional Legislation Related To The Use Of Similar Biological Medicinal Products: The Italian Case Study

Japanese regulation of biosimilar products: past experience and current challenges.

Seven biosimilar products have been approved in Japan since the March 2009 publication of the 'Guideline for quality, safety and efficacy assurance of biosimilar products' by the Ministry of Health, Labor and Welfare (MHLW). Four years previously, the 'Guideline on similar biological medicinal products' was issued in the European Union (EU), and 13 products as of February 2016 have been approved as biosimilar. The US Food and Drug Administration (FDA) approved the first biosimilar product in the US in March 2015 and final Guidance was issued at the end of April 2015. Over the past decade, the challenges regarding the development of biosimilar products have been discussed extensively. In this article, the data packages of biosimilar products in Japan are compared with those overseas in order to clarify the concepts used by the Japanese regulatory authority, i.e., the Pharmaceuticals and Medical Devices Agency (PMDA). The challenges in the development of biosimilar products in Japan are also addressed.

Biosimilar infliximab for the management of rheumatoid arthritis in France: what are the expected savings?

ObjectivesBiosimilar infliximab, the first similar biological medicinal product containing monoclonal antibodies to be commercialised, is likely to contribute to a significant reduction in healthcare costs. We aimed to assess the...

European medicines agency guideline for biological medicinal products: a further step for a safe use of biosimilars.

European medicines agency guideline for biological medicinal products: a further step for a safe use of biosimilars.

Biosimilars: the science of extrapolation

AbstractDespite the establishment of a specific approval pathway, the issuance of detailed scientific guidelines for the development of similar biological medicinal products (so-called “biosimilars”) and the approval of several biosimilars in the European Union, acceptance of biosimilars in the medical community continues to be low. This is especially true in therapeutic indications for which no specific clinical trials with the biosimilar have been performed and that have been licensed based on extrapolation of efficacy and safety data from other indications. This article addresses the concerns frequently raised in the medical community about the use of biosimilars in such extrapolated indications and explains the underlying scientific and regulatory decision making including some real-life examples from recently licensed biosimilars.

Applications of the Bayesian Prior Information to Evaluation of Equivalence of Similar Biological Medicinal Products

In 2014, there are a number of patents of best-selling biotech drugs around the world about to expire. Large commercial interests will inevitably set off international competition among major pharmaceutical companies. The European Union, the United States, and other countries with advanced medical techniques have paid a high degree of attention to biological similarity (biosimilarity) for drug development and market management and have started to take corresponding measures. Because of the diverse definitions of biosimilarity between countries, which can determine whether the medicines on sale are in the review of the base grant, the competent authority will also encounter varying degrees of standards. Governments should review the corresponding guidelines as soon as possible because many countries around the world have actively amended the law in response to management need of biological similarity. The similarity of biological drugs should be assessed by clinical trial under current regulations. Pharmaceutical companies try to lower the cost of generic drugs to increase the competitiveness of their products. To reduce the number of subjects in the clinical trials for development of generic drugs, we refer to the clinical trial for evaluation of bridging studies. Hsiao et al. (2007) has proposed the use of Bayes method in evaluation of bridging studies. Prior information on the original region is used to reduce the number of subjects to lower the cost of biosimilar drug development. Take the results of the approval biologics as a priori information, and the information is appropriate to be embedded into the model evaluating the similar products in order to reduce the sample size required for the assessment of the test sample.

Statistical considerations for the development of biosimilar products

As the patents of a growing number of biological medicines have already expired or are due to expire, it has led to an increased interest from both the biopharmaceutical industry and the regulatory agencies in the development and approval of biosimilars. With the high urgency, European Medicines Agency released the first general guideline on similar biological medicinal products in 2005 and specific guidelines for different drug classes subsequently and US Food and Drug Administration issued three draft guidelines in 2012 on biosimilar product development. A synthesized message from these guidance documents is due to the fundamental differences between small molecule drug products and biological products which are made of living cells, the generic versions of biological products are viewed as similar, instead of identical as the innovative drug product. Thus, more stringent requirement is needed to show no clinically meaningful differences between the biosimilar product and the reference product in terms of the safety, purity, and potency. In this article, we will briefly review statistical issues and challenges in development of biosimilars, including criteria for biosimilarity and interchangeability; selection of endpoints and determination of equivalence margins; equivalence versus non-inferiority; bridging and regional effect; and how to quantify totality-of-the-evidence.

A Consistency Approach for Evaluation of Biosimilar Products

Recently, biosimilars have attracted much attention from sponsors and regulatory authorities, while patents on early biological products will soon expire in the next few years. The European Medicines Agency (EMEA) of the European Union (EU) published a guideline on similar biological medicinal products for approval of these products in 2005. Based on the foundational principles of the EMEA guideline, biosimilars are expected to be similar, not identical, to the innovator biologics they seek to copy. In this article, we develop a consistency approach for assessment of similarity between a biosimilar product and the innovator biologic. A method for sample size determination for conducting a clinical trial to assess the biosimilar product is also proposed. A numerical example is given to illustrate applications of the proposed approach in different scenarios.

Clinical Development of Biosimilars: an Evolving Landscape

Biosimilars, or similar biological medicinal products, can provide a meaningful option for patients and physicians provided they deliver the therapeutic value of a reference product at a more modest cost. Unlike generic small-molecule drugs that require primarily the demonstration of pharmaceutical equivalence, the complex nature of protein therapeutics warrants a rigorous evaluation of both pharmaceutical and therapeutic equivalence to the reference product in an abbreviated clinical program. Furthermore, the lack of comprehensive structure-activity relationship data increases the burden on appropriately designed human clinical studies with predefined acceptance criteria to demonstrate the absence of clinically meaningful differences between the biosimilar and reference product. Although a number of biosimilar proteins have been approved, especially in Europe, issues on substitutability, extrapolation to other disease indications, and selection of reference standards and comparators, remains to be standardized at a global level.

Regulatory Considerations for Generic or Biosimilar Low Molecular Weight Heparins

The aim of the present paper is to address the legal aspects, technical requirements and possible conditions of use associated to low molecular weight heparin generics and biosimilars that are arriving to the market in United States and the European Union, respectively. To this end the concept of "similar biological medicinal product" that was coined in 2003 by the pharmaceutical legislation of the European Union is compared to the concept of generic in the United States and the concept of generic in the European Union. This different legal basis determines directly the technical requirements to obtain a marketing authorisation. Therefore, the chemical/biological, non-clinical and clinical requirements to demonstrate therapeutic equivalence are different in these two Regulatory Authorities, FDA and EMA. Consequently, the possible conditions of use are different. In the United States the products approved as generics by the FDA are considered interchangeable to the Reference Listed Drug. In contrast, the EMA legislation only deals with the approvability or prescribability of the medicines and it is a national / regional decision of the member States to consider these biosimilar products as interchangeable or not.

A patient-centred paradigm for the biosimilars market

Intr oduction In the history of medicine, biologicals are relatively new products. Biologicals developed in the 1980s produced an impact in nephrology, oncology, and other therapeutic areas. The expiration of intellectual property rights on originator biologicals created the possibility for development of ‘follow-on biologic’ products, based on the originators. The EU in 2005 initiated public discussion on guidelines for approval of such products [1], which it denominated as ‘similar biological medicinal products’ in the guideline but also referred to as ‘biosimilars’ in subsequent publications [2]. EMA approved its first biosimilar under these guidelines in 2006. Since then, many countries on all continents (besides Antarctica) have adopted similar biosimilar regulatory approval procedures, and the WHO has developed a guideline for development of such regulatory guidelines. Regulatory and industry conferences have addressed how to achieve the appropriate level of regulation for biosimilars [3]. One consulting company recently estimated the combined annual growth rate of the global biosimilars market at 52% for the time period 2010–15 [4].

Concept of biosimilar products in Jordan

After the expiration of patents on originator biological products, Jordanian local manufacturers and the agents of international pharmaceutical companies in Jordan started to submit registration dossiers for biosimilar products. The Jordan Food and Drug Administration (JFDA) is the national regulatory authority responsible for the registration of biosimilar products. Biosimilars are registered under the same regulations used for drugs until specific guidelines for registration of biological and biosimilar products are released. Those regulations are called Criteria of Registration of Drugs, Vaccines, Sera and Biological Products, the Renewal of its Registration and the Cancellation of Any of them which was published in the official gazette in 2004 under the Provisional Law Number 80 of the year 2001, Drug and Pharmacy Law and its amendments of the year 2003. Also, the JFDA follows the EMA guidelines on similar biological medicinal products for specific active biological substances for non-clinical and clinical studies requirements and the EMA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. A post marketing surveillance study is requested after a biosimilar product is authorized.The JFDA keeps pace with all advances in the regulatory issues related to biosimilars in order to be capable of authorizing biosimilar products with a safe, effective and good quality profile.

Similar biological medicinal products currently licensed in the European union - Overview of non-clinical study programs

In the EU, a regulatory framework has been established which defines general conditions for marketing authorisation approval of similar biological medicinal products (SBMPs). In addition, the framework provides product-class specific recommendations for non-clinical evaluation of specific SBMPs containing as active substance recombinant somatropin, granulocyte-colony stimulating factor (G-CSF), erythropoietin, interferon alpha, insulin or low molecular weight heparins.During the last years, a number of SBMPs have been succesfully licensed in the EU. This article summarizes the non-clinical evaluations performed for these medicinal products and provides a comparison with the current requests for non-clinical evaluation as laid down in the respective EU regulatory guidelines.

Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies [Draft

Biotechnology Law ReportVol. 30, No. 2 DocumentsGuideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies [Draft]Published Online:14 Apr 2011https://doi.org/10.1089/blr.2011.9970AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byThe Rise of Anti-TNF Biosimilars: Guidelines, Real-World Evidence, and Challenges to Acceptance4 November 2022 | EMJ GastroenterologyReal-world effectiveness and persistence of reference etanercept versus biosimilar etanercept GP2015 among rheumatoid arthritis patients: A cohort study3 October 2022 | Frontiers in Pharmacology, Vol. 13Monoclonal Antibodies for Cancer Treatment8 June 2022A randomized, double-blind, single-dose, two-way, parallel phase I clinical study comparing the pharmacokinetics and safety of adalimumab injecta and Humira® in healthy Chinese male volunteers30 June 2021 | Expert Opinion on Biological Therapy, Vol. 22, No. 2Analytical similarity assessment of MYL-1402O to reference Bevacizumab13 October 2021 | Expert Opinion on Biological Therapy, Vol. 22, No. 2Comparative biosimilar quality studies between a rituximab product and MabTheraJournal Of Advanced Pharmacy Education And Research, Vol. 11, No. 4Physicochemical analysis and biological characterization of FKB327 as a biosimilar to adalimumab4 June 2020 | Pharmacology Research & Perspectives, Vol. 8, No. 3Pharmacokinetic Similarity of ABP 710, a Proposed Biosimilar to Infliximab: Results From a Randomized, Single‐Blind, Single‐Dose, Parallel‐Group Study in Healthy Subjects19 October 2019 | Clinical Pharmacology in Drug Development, Vol. 9, No. 2Evaluation of Antibody Properties and Clinically Relevant Immunogenicity, Anaphylaxis, and Hypersensitivity Reactions in Two Phase III Trials of Tralokinumab in Severe, Uncontrolled Asthma16 January 2019 | Drug Safety, Vol. 42, No. 6The Emerging Treatment Landscape of Inflammatory Bowel Disease: Role of Innovator Biologics and Biosimilars11 December 2018 | EMJ GastroenterologyBiosimilar Law and Regulation: An Essential GuideSSRN Electronic Journal, Vol. 12 Volume 30Issue 2Apr 2011 InformationCopyright 2011, Mary Ann Liebert, Inc.To cite this article:Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies [Draft].Biotechnology Law Report.Apr 2011.235-242.http://doi.org/10.1089/blr.2011.9970Published in Volume: 30 Issue 2: April 14, 2011PDF download

Similar biological medicinal products: lessons learned and challenges ahead

The first similar biological medicinal products (or biosimilars) were approved in the European Union (EU) in 2006 in accordance to a regulatory framework published by the European Commission in 2003 and 2004. The term ‘similar biological’ or biosimilar was preferred instead of the term ‘biogeneric’ as, in contrast to small molecules in chemical drugs, due to the size and complexity of biological products, additional safety and efficacy studies would be needed to establish comparability to a reference product. Several product-specific guidelines have already been developed by the European Medicines Agency describing the requirements to establish comparability on quality, safety and efficacy to the reference product and some others are currently under development. Even though the harmonized European regulatory framework for biosimilars there appear to be marked differences among the EU countries in the perception of the value and use of biosimilars. Several factors have been considered as challenges to their wide use such as concerns about their safety and efficacy, pharmacovigilance, interchangeability and substitution, market competition, and extrapolation of indications. A proper knowledge of these issues is required to ensure an appropriate place on the market for these products.