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Buttel I.C.,Paul Ehrlich Institute | Chamberlain P.,NDA Advisory Board | Chowers Y.,Rambam Health Care Campus | Ehmann F.,European Medicines Agency EMA | And 21 more authors.
Biologicals | Year: 2011

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. © 2011.

Callreus T.,Danish Health and Medicines Authority | Schneider C.K.,Danish Health and Medicines Authority | Schneider C.K.,Twincore Center for Experimental | Schneider C.K.,European Medicines Agency EMA
Pharmaceutical Medicine | Year: 2013

Against a backdrop of increasing costs and poor productivity, the concept of 'regulatory science' has sometimes been invoked in recent years in discussions regarding regulation of pharmaceuticals. There is not one generally accepted definition of regulatory science; however, there are several proposed definitions centered on a common theme: the 'brand of science' (knowledge, tools, concepts, etc.) that underpins and evolves regulatory decision making. This article provides a short review of the origins and features of regulatory science in addition to an exploration of its current and potential future role in pharmaceutical medicine. Moreover, the article discusses how regulatory science differs from traditional academic science and how it is related to the concept of regulatory affairs. It is concluded that the emerging field of regulatory science is likely to influence the future shaping and implementation of laws and regulations. © 2013 Springer International Publishing Switzerland.

Greten T.F.,Hannover Medical School | Greten T.F.,Twincore Center for Experimental | Ormandy L.A.,Hannover Medical School | Ormandy L.A.,University of Gottingen | And 10 more authors.
Journal of Immunotherapy | Year: 2010

Immunotherapy represents a potential therapeutic option for patients with hepatocellular carcinoma (HCC). However, CD4CD25Foxp regulatory T cells, which suppress potential antigen-specific T-cell responses, are increased in patients with HCC and might impair the effect of an immune-based therapeutic approach. In this study, we demonstrate that depletion of regulatory T cells in vitro unmasks α-fetoprotein-specific T-cell responses in HCC patients. On the basis of these results, we performed a clinical trial, in which 13 patients with advanced HCC ineligible for any other type of treatment were treated with 150, 250, or 350 mg/m cyclophosphamide on day 1 and 29 to suppress regulatory T cells in these patients (NCT00396682). The primary end point of this trial was regulatory T-cell number and function. Low-dose cyclophosphamide treatment (150 and 250 mg/m) induced a decrease in the absolute and relative frequency of CD4CD25Foxp regulatory T cells in peripheral blood on days 8 and 29. Suppressor function of regulatory T cells was impaired after treatment of patients with 250 mg/m on days 8 and 21. Finally, α-fetoprotein-specific T-cell responses were unmasked in 6/13 treated patients. In summary, systemic treatment of HCC patients with low-dose cyclophosphamide decreases the frequency and suppressor function of circulating CD4CD25Foxp regulatory T cells in peripheral blood and could be used in combination with immunotherapeutic approaches in HCC. Copyright © 2010 by Lippincott Williams & Wilkins.

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