Christian K. Schneider

Biosimilars: what clinicians should know

Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biologic Medicinal Products of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators.

Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response

Drug regulatory agencies should ensure that the benefits of drugs outweigh their risks, but licensed medicines sometimes do not perform as expected in everyday clinical practice. Failure may relate to lower than anticipated efficacy or a higher than anticipated incidence or severity of adverse effects. Here we show that the problem of benefit–risk is to a considerable degree a problem of variability in drug response. We describe biological and behavioural sources of variability and how these contribute to the long-known efficacy–effectiveness gap. In this context, efficacy describes how a drug performs under conditions of clinical trials, whereas effectiveness describes how it performs under conditions of everyday clinical practice. We argue that a broad range of pre- and post-licensing technologies will need to be harnessed to bridge the efficacy–effectiveness gap. Successful approaches will not be limited to the current notion of pharmacogenomics-based personalized medicines, but will also entail the wider use of electronic health-care tools to improve drug prescribing and patient adherence.

Biosimilars—why terminology matters

volume 29 number 8 august 2011 nature biotechnology very often don’t have time to devote employees to outside projects, such as IMI. Our editorial attempted to highlight the problem that the innovative agenda of EFPIA members may not be as broad as the innovative agenda put forward by less established and smaller companies who seek to disrupt conventional approaches. For example, it is clear that cells derived from human induced pluripotent stem cells offer considerable potential in drug discovery screens and safety assessment, and this has been demonstrated by the investment by the pharmaceutical industry in these approaches in recent years. But what about the potential of such products as experimental therapies in themselves? Clearly, a focus for many SMEs and academic groups but not a major focus for many major pharmaceutical companies. Perhaps IMI could play a role in moving such unconventional approaches forward, especially if the funding and expertise from EU and EFPIA could be used to help SMEs focus their efforts to address the formidable manufacturing, regulatory and reimbursement issues that cell therapies face before reaching the market. biomarker candidates for drug-induced injury of the kidney, the liver and the vascular system and established a generic strategy to qualify biomarkers4, whereas the eTOX consortium (http://www.e-tox. net/consortium.html), which includes four IT solution SMEs, developed an innovative multi-scale modeling strategy allowing the in silico prediction of drug effects on the heart using electrocardiogram simulations5. In parallel, four education and training projects are running, covering different areas of pharmaceutical sciences, including pharmacovigilance, of direct relevance to industry and regulatory authorities. Therefore, the alarmist and negative description of IMI reported in this journal does not reflect reality. In an era where biopharmaceutical companies rely more and more on noncompetitive research and open collaboration to develop new models for drug development, IMI offers unique opportunities for academic groups and SMEs interested in translating results of their endeavors into innovative therapies. The update of the IMI Scientific Research Agenda has just been completed and will result in a series of even more ambitious projects based on sharing of data and know-how to address major unmet medical needs. The currently running 4th Call for Proposals (Table 1) already contains two ‘Think Big’ projects with a transformational potential: the first aims at developing a European framework for patient-level health information, which will be exploited for investigations on major diseases in adult and pediatric populations; the second will focus on the use of induced pluripotent stem cells derived from patients as innovative tools for drug discovery and safety assessment. The budget of each project will be around €50 (

Challenges with advanced therapy medicinal products and how to meet them

70) million, with equal contributions from the European Commission and companies in EFPIA (the European Federation of Pharmaceutical Industries and Associations), the latter in the form of inkind contributions. More than ever, the European Commission and EFPIA are determined to stimulate industry, including SMEs, and academia to collaborate on large-scale ‘game changing’ IMI projects to foster scientific talents and strengthen the ecosystem of pharmaceutical research across the European Union, for the ultimate benefit of patients.

Risk of tumorigenicity in mesenchymal stromal cell–based therapies—Bridging scientific observations and regulatory viewpoints

Advanced therapy medicinal products (ATMPs), which include gene therapy medicinal products, somatic cell therapy medicinal products and tissue-engineered products, are at the cutting edge of innovation and offer a major hope for various diseases for which there are limited or no therapeutic options. They have therefore been subject to considerable interest and debate. Following the European regulation on ATMPs, a consolidated regulatory framework for these innovative medicines has recently been established. Central to this framework is the Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA), comprising a multidisciplinary scientific expert committee, representing all EU member states and European Free Trade Association countries, as well as patient and medical associations. In this article, the CAT discusses some of the typical issues raised by developers of ATMPs, and highlights the opportunities for such companies and research groups to approach the EMA and the CAT as a regulatory advisor during development.

Toward biosimilar monoclonal antibodies

In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.

Clinical development of advanced therapy medicinal products in Europe: evidence that regulators must be proactive.

To what extent is the existing framework for biosimilars in Europe likely to be applicable to monoclonal antibodies?

Development and Regulation of Biosimilars: Current Status and Future Challenges

Advanced therapy medicinal products (ATMPs), defined as gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products, and tissue-engineered products (TEPs),1,2 constitute a major class of innovative therapeutics that are being investigated as treatments for several diseases. Despite the success of many such products in animal studies, few have reached more advanced regulatory milestones in Europe (Figure 1), such as ATMP Certification from the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA),3 regulatory scientific advice from the EMA,4 or a marketing authorization application at the EMA.5 Therefore, there is a need to identify the major stakeholders in the development of such products and to investigate why they have been unable to move these products farther down the development pipeline. As members of the CAT and EMA, we analyzed the data in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database (https://eudract.ema.europa.eu). Analysis of 318 ATMP trials performed between 2004 and 2010 revealed that the main sponsors are academia, charities, and small companies. This may have implications for the further evolution of the regulatory framework for ATMPs given that such stakeholders often have limited financial resources or regulatory expertise, leading to a “translational gap” that must be proactively closed by regulators.

Setting the stage for biosimilar monoclonal antibodies

Biologic medicinal products developed via rDNA technology as recombinant protein-based medicines that have been in clinical use since the early 1980s as original biopharmaceuticals have greatly contributed to the therapy of severe metabolic and degenerative diseases. The recent expiration of the data protection or patents for most of them created opportunities for the development of copy versions of original biopharmaceuticals with similar biologic activity (termed biosimilars). Production of these new products is expected to meet worldwide demand, promote market competition, maintain the incentives for innovation, and sustain the healthcare systems. The licencing of these products, however, relies on the experience gained with the original biopharmaceuticals. Critical issues related to this class of medicinal products include their terminology (to avoid confusion with generics and non-innovator copy versions that have not been tested according to the biosimilar guidelines), manufacturing, and regulation. The European Union (EU) has been the first to establish a regulatory framework for marketing authorization application (MAA) and has named these products biosimilars, a term also recently adopted by the US FDA. Unlike the conventional, more common small molecular weight human medicines and chemical generics, protein-based medicines exhibit higher molecular weight, complexity in structure and function that can be affected by changes in the manufacturing process. Therefore, biosimilars represent a relatively heterogeneous class of medicinal products that make their regulation quite challenging. According to the current understanding in the EU, a biosimilar is a copy version of an already authorized biopharmaceutical (or reference product) with similar biologic activity, physicochemical characteristics, efficacy, and safety, based on a full comparability exercise at quality, preclinical and clinical level to ensure similar efficacy and safety. Guidance has been provided through several Committee for Medicinal Products for Human Use (CHMP) guidelines as well as individual scientific advice requested from the European Medicines Agency (EMA) by various companies for the development and regulation of biosimilars. This review is mainly focused on the current status of regulation of biosimilars in the EU as well as on future challenges lying ahead for the improvement of the requirements needed for the marketing authorization of biosimilars. Emphasis is given on the quality requirements concerning these medicinal products (biologics).

The risks of risk aversion in drug regulation

With the first marketing authorization application for a biosimilar monoclonal antibody now under consideration at the European Medicines Agency, what are the critical issues for regulators?