Summary of the diverse situation of similar biotherapeutic products in the selected countries (August 2010)

The WHO guidelines on evaluating similar biotherapeutic products (SBPs) were adopted by the Expert Committee on Biological Standardization in 2009. The fundamental messages of the guidelines are that a) generic approach is not suitable for licensing SBPs, b) only products that have been subjected to a comparability exercise and show similarity to the reference biotherapeutic product (RBP) in terms of their quality, safety and efficacy are defined as SBPs, and c) the products that are not shown to be similar to the originator products as indicated in the guidelines should neither be described as "similar" nor called SBPs. In view of these, the products which have not been subjected to a head to head comparison with the RBP should be referred to as another term, e.g. 'non-innovator' therapeutic products. In order to review the current situation in each country, a survey was planned in line with the implementation workshop of the guidelines in August 2010. The results show that the diversity of regulatory framework for licensing SBPs and the ambiguous use of the terms, 'similar' or 'generic', present considerable challenges for the future use of SBPs.     

Evaluation of similar biotherapeutic products (SBPs): scientific principles and their implementation

The availability of biotherapeutic products to patients has a major impact on the success in treating many life-threatening and chronic diseases. These products are often derived by recombinant DNA technology and are expensive for the majority of patients who need them most. Increasing numbers of patents/data protection are now expiring and biologicals "similar" to the originators (innovative products) are coming to the market. This process is seen as a mechanism for increasing the access to biotherapeutic products which are very much needed for the treatment of chronic diseases worldwide. The emergence of Similar Biological Products (SBPs) has created numerous challenges in developing, licensing, and using these important products. From a public health perspective, the overall expectation is that similar products will be available at an affordable price and will increase patients' access to the therapy. In response to the requests for assistance in defining regulatory requirements for SBPs, the WHO Expert Committee on Biological Standardization (ECBS) adopted the new WHO Guidelines for evaluation of SBPs in October 2009. This article provides a brief account of the WHO initiative to assist its member states to establish national requirements for the regulatory oversight of SBPs. The aim of the article is to inform its readers of the current status of WHO Guidelines on the evaluation of similar biotherapeutic products and of the plan to strengthen national regulatory requirements to assure quality, safety and efficacy of similar biotherapeutic products at the global level.     

WHO informal consultation on regulatory evaluation of therapeutic biological medicinal products held at WHO Headquarters, Geneva, 19-20 April 2007.

This report reflects the discussion and conclusions of an informal consultation held on 19-20 April 2007 at the World Health Organization concerning the regulatory evaluation of therapeutic biological medicinal products. The objectives of this meeting were to discuss the current status of so-called "similar" biological medicinal products (biosimilars) and to review regulatory pathways and challenges in evaluating the quality, safety and efficacy of these products. Biosimilars are products that are subject to licensing with a reduced data package due to a proven 'similarity' to the licensed reference product. The meeting was attended by experts in biotherapeutics from regulatory agencies, industry and academia representing 16 countries worldwide. Dr. Elwyn Griffiths (Canada) acted as Chairman and Dr. James Robertson (UK) was the Rapporteur. The meeting strongly focused on the usage of biosimilars and the current regulatory situation in many different countries. The application of International Nonproprietary Names (INN) to biosimilars, their potential immunogenicity, and WHO international standards and reference materials were also discussed, alongside presentations from the innovator and generic manufacturing industries. The consultation recognized the importance of the terminology as well as a definition of biosimilars for future considerations of these products. However, achieving a global consensus on the terminology for these new challenging products was not attempted at the Consultation, and it was decided that a future WHO working group should act on this issue as a next step. For purposes of this meeting report only, the term 'biosimilars' is temporarily used to refer to this category of products. It became clear that biotherapeutics authorized on the basis of a reduced data package are available and being used in some countries, with more appearing on the market. The existence of divergent approaches to the regulatory oversight of biosimilars in different countries revealed a need for defining regulatory expectations for these products at the global level. While many countries are following the guideline developed within the EU for quality aspects, discrepancies remain regarding the non-clinical and clinical studies of these products. The Consultation recommended that the WHO should develop a guideline in this area in order to provide a framework for the development of regulatory pathways for these products worldwide. For this purpose, agreement on the scope, definition and terminology of these products was deemed necessary. The interchangeability and substitution of products were also flagged as areas in need of harmonization. A WHO working group should be established to develop a guideline that would promote global consensus on the regulation of biosimilars, assist in their registration and enhance the availability of safe and effective biosimilar products worldwide.     

Biosimilars clinical development program: confirmatory clinical trials: a virtual/simulated case study comparing equivalence and non-inferiority approaches

As part of long term commitment of the Biologicals and Vaccines Committee (B&V) of the International Federation of Pharmaceutical Manufacturers and Association (IFPMA) to provide expert input to the WHO on their recently finalized GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs), and in response to WHO's request, the IFPMA B&V prepared a clinical case study at a recent WHO workshop in Seoul, Korea. The case study, presented by Mark Fletcher on behalf of B&V, involved a model scenario for a clinical efficacy trial to support the approval of a Similar Biotherapeutic Product (SBP) as part of the required comparative clinical program against a Reference Biotherapeutic Product (RBP). A key goal was to understand and illustrate key clinical and statistical principles, and considerations described in the WHO Guidance for regulatory authorities when designing and implementing WHO guidelines and post-approval regulatory oversight for SBPs. Using this model SBP/RBP pair, an interactive discussion was carried out among the workshop participants on the pros and cons of using equivalence vs. non-inferiority designs to assess the two products' similarity. Through discussion of the case, the complexity of demonstrating similar efficacy and safety of a SBP vs. RBP for biotherapeutic products is outlined and discussed in the context of the key principles laid out in the recently published WHO GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs). The exercise illustrates the need for a case-by-case approach when interpreting clinical data from SBP dossiers to adequately assure similar efficacy and safety of SBPs for any studied indication.     

Stability evaluation of vaccines: WHO approach

The stability of vaccines has a major impact on the success of immunization programmes worldwide. In line with this, clear definition of the stability characteristics of a vaccine is of critical importance. One of the concerns at country level is whether vaccines will remain potent on its way from the manufacturer, through the distribution channels, to the final users and vaccine recipients. In response to the requests for assistance in defining stability profile of vaccines, the Expert Committee on Biological Standardization (ECBS) in October 2006 agreed that new WHO guidelines be established on stability evaluation of vaccines (http://www.who.int/biologicals/publications/trs/areas/vaccines/stability/en/index.html). This document applies to all vaccines against infectious diseases. The aim of this guideline is to provide the scientific basis and guiding principles for evaluation of vaccine stability for the purpose of clinical trial approval, licensing, and post-licensure monitoring. As part of its initiative to promote use of vaccines of assured quality, WHO emphasizes the role of National Regulatory Authorities (NRAs) and National Control Laboratories (NCLs) in overall vaccine evaluation, including stability assessment. While recognizing that manufacturers are responsible for the quality of the vaccines they produce, compliance with vaccine quality specifications is part of regulatory oversight. This article provides basic information about WHO international standards as well as key definitions and principles for stability evaluation of vaccines that are elaborated in detail in the above mentioned guidance document.     

Evaluation of cell substrates for the production of biologicals: Revision of WHO recommendations: Report of the WHO Study Group on Cell Substrates for the Production of Biologicals, 22–23 April 2009, Bethesda,USA

Evaluating cell substrates for producing vaccines and other biologicals is one of the critical aspects in assuring quality and safety of these products. As part of its mission in setting standards for biological products, WHO provides recommendations for manufacturing and evaluating biologicals. Regular updates of the guidance documents are important to manufacturers and regulators worldwide. WHO Expert Committee on Biological Standardization (ECBS) identified a need for revising the requirements for cell substrates (WHO TRS 878, annex 1). In response, WHO established a Study Group (SG) in 2006 that prepared an updated set of recommendations for using cell substrates for the production of biologicals. A summary of the proposed changes that the SG made in 2007 is available at WHO web site (http://www.who.int/biologicals/publications/meetings/areas/vaccines/cells/en/index.html). Draft revised recommendations were circulated to regulators, manufacturers and other experts for comments in April 2009.The SG held its third meeting on 22–23 April 2009 to review progress in the revision and to propose further improvements. In addition, the experts discussed the need for reference preparations, reference cell banks, and standardization of testing methodologies. The SG proposed clarifications of the rationale for in vivo testing as well as the potential for applying new methods for in vitro testing for detecting microbial agents. In line with this, WHO should conduct review of the current manufacturers' practice in using tests for microbial agents and interpreting these results. Additionally, WHO should take a lead in developing an International Standard for nucleic acid amplification test (NAT) for detecting mycoplasma contamination in cell substrates. WHO Collaborating Centers will lead this initiative, involving other relevant institutions in this area. Finally, advice on the replacement of the WHO Vero reference cell bank 10–87 with respect to the source of cells and re-characterization of the bank was provided. The intended use of the replacement cell bank would be the same as for the current cell bank, which is to serve as a source of well-characterized cells for establishing master cell banks for the production of biologicals. The SG will report outcomes of its discussion to the ECBS at its next meeting in October 2009 for further considerations and advice regarding the proposed course of action.     

China's perspective on similar biotherapeutic products

In order to ensure most Chinese patients, particularly in the population with relatively low incomes, have access to safe, low cost, effective and quality-assured medicines, a number of "stand-alone" biological products, which have good quality, safety and efficacy have been marketed in China. Many countries and regions' regulatory agencies are actively engaging in the development of bio-similar guidance and documents, which is being coordinated by WHO. As a major developing country of new drug development, China is now working hard to promote the process of new similar biotherapeutic products (SBPs) approval and also actively involved in developing and updating technical documents.     

Report on the international workshop on alternative methods for human and veterinary rabies vaccine testing: State of the science and planning the way forward

Potency testing of most human and veterinary rabies vaccines requires vaccination of mice followed by a challenge test using an intracerebral injection of live rabies virus. NICEATM, ICCVAM, and their international partners organized a workshop to review the availability and validation status of alternative methods that might reduce, refine, or replace the use of animals for rabies vaccine potency testing, and to identify research and development efforts to further advance alternative methods. Workshop participants agreed that general anesthesia should be used for intracerebral virus injections and that humane endpoints should be used routinely as the basis for euthanizing animals when conducting the mouse rabies challenge test. Workshop participants recommended as a near-term priority replacement of the mouse challenge with a test validated to ensure potency, such as the mouse antibody serum neutralization test for adjuvanted veterinary rabies vaccines for which an international collaborative study was recently completed. The workshop recommended that an in vitro antigen quantification test should be a high priority for product-specific validation of human and non-adjuvanted veterinary rabies vaccines. Finally, workshop participants recommended greater international cooperation to expedite development, validation, regulatory acceptance, and implementation of alternative test methods for rabies vaccine potency testing.     

浅谈WHO国家疫苗监管体系评估及其上市许可板块要求

通过卫生组织国家疫苗监管体系(National Regulatory Authority)评估是一个国家疫苗具备参与联合国全球采购资格的必要条件。本文对WHO国家疫苗监管体系评估整体加以简述,重点对上市许可板块指标进行归纳,通过探讨WHO国家疫苗监管体系评估上市许可部分的管理理念,以期为疫苗监管相关部门加强自身管理提升监管质量和效率有所提示。     

Intended use of reference products & WHO International Standards/Reference Reagents in the development of similar biological products (biosimilars)

Reference Products and WHO International Standards/Reference Reagents have roles to play in the development and characterization of similar biological products (SBPs). However, these roles are distinct and non-interchangeable. The uses of these materials and their limitations are considered in this paper.     

Experience of reviewing the follow-on biologics including Somatropin and erythropoietin in Japan

To share the experience of reviewing clinical data required for the licensing of follow-on biologic products (biosimilar products and similar biotherapeutical products as EU and WHO terminology, respectively) in Japan, the data packages of two follow-on biologics, "Somatropin BS s.c. [Sandoz] (Omnitrope?)" and "Epoetin alfa BS [JCR]", which have been recently approved in Japan according to the "Guidelines for the Quality, Safety and Efficacy Assurance of Follow-on Biologics" published on March 4th 2009, are described. The clinical data package and indication of Somatropin BS/Omnitrope(?) were different in each country. In case of Epoetin alfa BS [JCR], non-clinical and clinical data-package was different from those of erythropoietin biosimilar products approved in EU. Submission of post-marketing surveillance plans for both products was required. Even though there seem to be differences in data requirements by each national regulatory authority, the accumulation of experience will provide the rationale and consensus on how to design the clinical trials for follow-on biologics.     

WHO technical workshop on stability of reference materials for biological medicines and in vitro diagnostics, Geneva, Switzerland, 28–29 November 2005

In November 2005, the World Health Organization convened an informal technical workshop on the stability of reference materials for biological medicines and in vitro diagnostics. The meeting was attended by experts from WHO collaborating centres in the area of biological standardization, national control laboratories, industries and other relevant organizations. The consultation group discussed current practices and approaches to predicting and monitoring the stability of biological reference materials. The group agreed to the need for establishing a working group (i) to continue dialogue on potential issues encompassing the principles, strategies and practicality for assuring the stability of WHO international reference standards for biological medicines and in vitro diagnostics and (ii) to develop more detailed guidance for assessment of the stability of WHO international biological reference materials.     

Clinical programs in the development of similar biotherapeutic products: rationale and general principles

Similar biotherapeutic products (SBPs) or biosimilars are biologics developed by pharmaceutical manufacturers to match originator biologics that have been on the market for a long time and lost their exclusivity (patent and market protection). The recently issued WHO guidelines on evaluation of SBPs provide clear guidance for manufacturers and regulators on how to develop and gain approval for these products. The present contribution illustrates the rationale for and general principles of the clinical programs used in the development of SBPs, taking the example of the three biosimilar products developed and marketed in Europe by Sandoz, namely growth hormone (Omnitrope?, the first ever EU biosimilar approval), erythropoietin α (Binocrit?), and filgrastim (Zarzio?).     

The WHO network of collaborating centres on standardization and regulatory evaluation of vaccines

WHO Collaborating Centres (CCs) form part of an international collaborative network set up by WHO in support of its mandated programme at the country, intercountry, regional, interregional and global levels, as appropriate. As part of its mandate in the area of biologicals, WHO has broadened the scope of its work and has expanded the range of activities devoted to the establishment of international standards for vaccines. In line with global immunization goals, the need for standards for evaluation of quality, safety and efficacy of new vaccines, as well as those that have been in use for a long time, has significantly increased. Furthermore, complex issues related to new production methodologies, more sophisticated techniques for characterization and laboratory testing, and for nonclinical and clinical evaluation of vaccines have raised a number of regulatory challenges for WHO when requested to assist its Member States. In this context, CCs in the area of standardization of vaccines and biotherapeutics (excluding blood products) have provided technical assistance and have broadened the scope of their work over time. In the area of standardization and regulatory evaluation of vaccines, WHO currently has six CCs as well as one candidate centre for which the designation process has been initiated and a further three candidate centres with great potential. The purpose of the meeting held on 24–26 April 2012 was to improve understanding of WHO's priorities in setting standards, to facilitate their implementation, and to increase transparency of the roles and responsibilities of CCs. The meeting was also an excellent opportunity to explore possibilities for improving collaboration between WHO and CCs, as well as among CCs themselves by working as a CC network. All CCs expressed a wish for increased interaction, information-sharing, collaboration and other ways of working together that may lead to cross-fertilization between the CCs. Synergy was recognized as a significant mechanism for leveraging existing resources in responding to global public health challenges and in addressing WHO's priorities. Agreement was reached for operating as a network of CCs.     

Appraisal of WHO Guidelines in Maternal Health Using the AGREE II Assessment Tool

In 2007, the World Health Organization (WHO) received a criticism for a lack of transparency and systematic methods in the development of guidelines, which were at that time perceived as substantially driven by expert opinion. In this paper we assessed the quality of maternal and perinatal health guidelines developed since then. We used the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool to evaluate the quality of methodological rigour and transparency of four different WHO guidelines published between 2007 and 2011. Our findings showed high scores among the most recent guidelines on maternal and perinatal health suggesting higher quality. However, there is still potential for improvement, especially in including different stakeholder views, transparency of guidelines regarding the role of the funding body and presentation of the guideline document.     

Coding and traceability for cells,tissues and organs for transplantation

Modern transplantation of cells, tissues and organs has been practiced within the last century achieving both life saving and enhancing results. Associated risks have been recognized including infectious disease transmission, malignancy, immune mediated disease and graft failure. This has resulted in establishment of government regulation, professional standard setting and establishment of vigilance and surveillance systems for early detection and prevention and to improve patient safety. The increased transportation of grafts across national boundaries has made traceability difficult and sometimes impossible. Experience during the first Gulf War with miss-identification of blood units coming from multiple countries without standardized coding and labeling has led international organizations to develop standardized nomenclature and coding for blood. Following this example, cell therapy and tissue transplant practitioners have also moved to standardization of coding systems. Establishment of an international coding system has progressed rapidly and implementation for blood has demonstrated multiple advantages. WHO has held two global consultations on human cells and tissues for transplantation, which recognized the global circulation of cells and tissues and growing commercialization and the need for means of coding to identify tissues and cells used in transplantation, are essential for full traceability. There is currently a wide diversity in the identification and coding of tissue and cell products. For tissues, with a few exceptions, product terminology has not been standardized even at the national level. Progress has been made in blood and cell therapies with a slow and steady trend towards implementation of the international code ISBT 128. Across all fields, there are now 3,700 licensed facilities in 66 countries. Efforts are necessary to encourage the introduction of a standardized international coding system for donation identification numbers, such as ISBT 128, for all donated biologic products.     

Next generation and biosimilar monoclonal antibodies: Essential considerations towards regulatory acceptance in Europe; February 3-4, 2011; Freiburg,Germany

The “Next Generation and Biosimilar Monoclonal Antibodies: Essential Considerations Towards Regulatory Acceptance in Europe” workshop, organized by the European Centre of Regulatory Affairs Freiburg (EUCRAF), was held February 3-4, 2011 in Freiburg, Germany. The workshop attracted over 100 attendees from 15 countries, including regulators from 11 agencies, who interacted over the course of the two days. The speakers presented their authoritative views on monoclonal antibodies (mAbs) as attractive targets for development, the experience to date with the regulatory process for biosimilar medicinal products, the European Medicines Agency draft guideline on biosimilar mAbs, as well as key elements in the development of mAbs. Participants engaged in many lively discussions, and much speculation, on the nature of the quality, non-clinical and clinical requirements for authorization of biosimilar mAbs.     

Considerations on photochemical genotoxicity. II: report of the 2009 International Workshop on Genotoxicity Testing Working Group

A workshop to reappraise the previous IWGT recommendations for photogenotoxicity testing [E. Gocke, L. Muller, P.J. Guzzie, S. Brendler-Schwaab, S. Bulera, C.F. Chignell, L.M. Henderson, A. Jacobs, H. Murli, R.D. Snyder, N. Tanaka, Considerations on photochemical genotoxicity: report of the International Workshop on Genotoxicity Test Procedures working group, Environ. Mol. Mutagen., 35 (2000) 173-184] was recently held as part of the 5th International Workshop on Genotoxicity Testing (IWGT) meeting in Basel, Switzerland (August 17-19, 2009). An Expert Panel was convened from regulatory, academic and industrial scientists (with several members serving on the original panel) and chaired by Dr Peter Kasper (BfArM, Germany). The aim of the workshop was to review progress made in photo(geno)toxicity testing over the past decade; a period which saw the introduction of several regulatory photosafety guidances in particular in Europe and the USA. Based on current regulatory guidelines a substantial proportion of compounds trigger the requirements for photosafety testing. Moreover, there has been growing concern within industry about the performance of the in vitro photosafety tests in the "real world" of compound development. Therefore, the expert group reviewed the status of the current regulatory guidance's and the impact these have had on compound development in the context of the various triggers for photosafety testing. In addition, the performance of photogenotoxicity assays (old and new) was discussed, particularly in view of reports of pseudophotoclastogencity. The Expert Panel finished with an assessment of the positioning of photogenotoxicity testing within a photosafety testing strategy. The most significant conclusion made by the Expert Panel was that photogenotoxicity testing should no longer be recommended as part of the standard photosafety testing strategy. In addition, progress was made on the refinement of triggers for photosafety testing. For example, there was support for harmonisation of methods to determine the Molar Extinction Coefficient (MEC) and a consensus agreement that there should be no requirement for testing of compounds with a MEC<1000Lmol(-1)cm(-1).     

WHO Study Group on cell substrates for production of biologicals, Geneva, Switzerland, 11–12 June 2007

For many years, the World Health Organization (WHO) has provided global leadership in defining technical specifications for quality assurance and safety of biological medicines produced in cell substrates. Current WHO requirements for the use of animal cells as substrates for production of vaccines and other biologicals were adopted by the WHO Expert Committee on Biological Standardization in 1996 (WHO TRS 878). Since then, significant progress especially in the development of vaccines in novel continuous cell lines of mammalian origin as well as in insect cells has been made and consequently there is an increasing need for the re-evaluation of existing criteria for the acceptability of such cell lines. In addition there is also a need to consider new issues in cell substrate safety arising from these new cell types and developments in technology and scientific knowledge. In response to these demands, the WHO Study Group on Cell Substrates was formed in 2006 to initiate revision of WHO requirements and to address the need for further research in this area. At its second meeting on 11-12 June 2007, the Study Group reviewed scientific data that would form the basis for new recommendations and made a number of proposals for further investigations. The Study Group is working on the preparation of a revised WHO document, and a broad consultation with regulators, manufacturers, and other relevant parties is planned for 2008.