[Regulatory aspects of biosimilars. Myths and facts]. / Regulatorische Aspekte zu Biosimilars. Mythen und Fakten.

BACKGROUND: Biosimilars are currently a hot topic and there are many unsolved questions, misunderstandings and sometimes considerable uncertainty, especially among clinicians and patients. Regulatory agencies, such as the European Medicines Agency (EMA) issue guidelines for the development and approval of biosimilars, which are based on scientific principles. OBJECTIVE: This article addresses some of the frequently noted misunderstandings and misperceptions. For example, why biosimilars are (or can only be) "similar" but not "identical" compared to the original pharmaceutical product, and aspects, such as the pharmaceutical quality of biosimilars, immunogenicity and the approval process for biosimilars are highlighted.

Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations.

Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.

Gatekeepers and enablers: how drug regulators respond to a challenging and changing environment by moving toward a proactive attitude.

This article analyzes the role of regulatory authorities in facilitating innovation in the pharmaceutical sector. We describe how regulators are expanding their role to be not only gatekeepers but also enablers of development. They have already responded to the challenging and changing environment by moving toward a proactive attitude beyond evaluation of products, thereby more actively contributing to their development. Regulators have to continuously evolve their knowledge and standards alongside evolution in science. Creation of supportive regulatory frameworks and multistakeholder interaction will help address unmet regulatory needs.

Establishment of the first international repository for transfusion-relevant bacteria reference strains: ISBT working party transfusion-transmitted infectious diseases (WP-TTID), subgroup on bacteria.

BACKGROUND: Bacterial contamination of platelet concentrates (PCs) still remains a significant problem in transfusion with potential important clinical consequences, including death. The International Society of Blood Transfusion Working Party on Transfusion-Transmitted Infectious Diseases, Subgroup on Bacteria, organised an international study on Transfusion-Relevant Bacteria References to be used as a tool for development, validation and comparison of both bacterial screening and pathogen reduction methods. MATERIAL AND METHODS: Four Bacteria References (Staphylococcus epidermidis PEI-B-06, Streptococcus pyogenes PEI-B-20, Klebsiella pneumoniae PEI-B-08 and Escherichia coli PEI-B-19) were selected regarding their ability to proliferate to high counts in PCs and distributed anonymised to 14 laboratories in 10 countries for identification, enumeration and bacterial proliferation in PCs after low spiking (0·3 and 0·03 CFU/ml), to simulate contamination occurring during blood donation. RESULTS: Bacteria References were correctly identified in 98% of all 52 identifications. S. pyogenes and E. coli grew in PCs in 11 out of 12 laboratories, and K. pneumoniae and S. epidermidis replicated in all participating laboratories. The results of bacterial counts were very consistent between laboratories: the 95% confidence intervals were for S. epidermidis: 1·19-1·32 × 10(7) CFU/ml, S. pyogenes: 0·58-0·69 × 10(7) CFU/ml, K. pneumoniae: 18·71-20·26 × 10(7) CFU/ml and E. coli: 1·78-2·10 × 10(7) CFU/ml. CONCLUSION: The study was undertaken as a proof of principle with the aim to demonstrate (i) the quality, stability and suitability of the bacterial strains for low-titre spiking of blood components, (ii) the property of donor-independent proliferation in PCs, and (iii) their suitability for worldwide shipping of deep frozen, blinded pathogenic bacteria. These aims were successfully fulfilled. The WHO Expert Committee Biological Standardisation has approved the adoption of these four bacteria strains as the first Repository for Transfusion-Relevant Bacteria Reference Strains and, additionally, endorsed as a project the addition of six further bacteria strain preparations suitable for control of platelet contamination as the next step of enlargement of the repository.

[Report from the Committee for Advanced Therapies (CAT). Pitfalls on the way from concept to medical treatment with advanced therapy medicinal products]. / Erfahrungsbericht aus dem Ausschuss für neuartige Therapien (CAT). Fallstricke auf dem Weg vom Konzept zur medizinischen Anwendung neuartiger Therapien.

Advanced therapy medicinal products (ATMP) are highly innovative and complex medicines. They comprise gene therapy medicinal products, somatic cell therapy medicinal products, and tissue-engineered products (TEP). With the European Regulation on ATMP that came into force in 2008, a consolidated regulatory framework was created, where the Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA) plays a central role. This article discusses pitfalls and challenges that the CAT has experienced in its discussions of various procedures. Often ATMPs are developed by small and medium-sized enterprises (SME) which also face nonscientific challenges. The CAT wishes to meet these challenges on a scientific and regulatory level during its 2010-2015 work program.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.

[Problems in microbial safety of advanced therapy medicinal products. Squaring the circle]. / Probleme der mikrobiellen Sicherheit bei neuartigen Therapien. Die Quadratur des Kreises.

Today, sterility of parenteral drugs is practically guaranteed. Well-defined procedures in the pharmaceutical industry enable effective protection against contamination by bacteria and fungi. In contrast, problems regarding microbial safety of advanced therapy medicinal products (ATMPs), especially of cell therapeutics, are at best only partially solved. The latter should be understood as a challenge for manufacturers, regulators, and physicians. Many of the manufacturing principles mentioned above are not applicable in production of cell therapeutics. Sterility of source materials cannot be guaranteed and the hitherto known procedures for sterilization are, as a rule, not feasible. Thus, the sterility of the final product cannot be guaranteed. Considering the extremely short shelf life of many cell therapeutics, sometimes only a few hours, the results from established methods for sterility testing are often available too late. Furthermore, the sterility of a test sample does not indicate sterility of the whole product. In most cases, conventional methods for pyrogen testing are not applicable for ATMPs. This paper demonstrates relevant limitations regarding microbial safety and pyrogenicity. Possibilities to overcome these problems are discussed and some novel solutions are proposed.

[Clinical trials with advanced therapy medicinal products]. / Klinische Prüfung mit Arzneimitteln für Neuartige Therapien.

For advanced therapies, the same basic principles for assessment apply as for any other biotechnological medicinal product. Nevertheless, the extent of data for quality, safety, and efficacy can be highly specific. Until recently, advanced therapies were not uniformly regulated across Europe, e.g., tissue engineered products were regulated either as medicinal products or medical devices. Thus, for some products no data from clinical studies are available, e.g., for autologous chondrocyte products. The draft guideline on Good Clinical Practice for clinical trials with advanced therapies describes specific additional requirements, e.g., ensuring traceability. Most clinical studies with advanced therapies in Germany are still in early phase I or II trials with highly divergent types of products and clinical indications. The Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMEA) has been established to meet the scientific and regulatory challenges with advanced therapies.

[After the TGN1412 incident. Principles for assessment of first-in-man trials with monoclonal antibodies by the Paul Ehrlich Institute]. / Nach dem TGN1412-Zwischenfall. Prinzipien der Bewertung von First-in-Man-Studien mit monoklonalen Antikörpern durch das Paul-Ehrlich-Institut.

The use of monoclonal antibodies has led to new therapeutic possibilities for many clinical conditions. However, their application also bears risks, as demonstrated by the acute occurrence of a cytokine storm following administration of TGN1412, an anti-CD28 superagonist, in March 2006. This article highlights the principles of the Paul-Ehrlich-Institut (PEI) for the scientific assessment of first-in-man clinical trial applications for monoclonal antibodies. These principles are implemented as a standard operating procedure in the PEI Quality Management System and are intended as a supplement specific to monoclonal antibodies to the published general guideline issued by the Committee for Medicinal Products for Human Use (CHMP). Central aspects are the identification of risk factors for monoclonal antibodies based on defined criteria, since not every novel monoclonal antibody represents a risk per se. Furthermore, a PEI expert group that supports the scientific assessment procedure has been founded.

Safety of phase I clinical trials with monoclonal antibodies in Germany--the regulatory requirements viewed in the aftermath of the TGN1412 disaster.

This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.