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Weise M.,Bundesinstitut For Arzneimittel Und Medizinprodukte | Bielsky M.-C.,Medicines and Healthcare Products Regulatory Agency | De Smet K.,Federal Agency for Medicines and Health Products | Ehmann F.,European Medicines Agency | And 16 more authors.
Blood | Year: 2012

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. © 2012 by The American Society of Hematology.


Mastelic B.,University of Geneva | Garcon N.,Glaxosmithkline | Del Giudice G.,Novartis | Golding H.,U.S. Food and Drug Administration | And 3 more authors.
Biologicals | Year: 2013

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/. © 2013.


PubMed | Chinese National Center for Safety Evaluation for Drugs, Wyss Institute for Biologically Inspired Engineering, Massachusetts Institute of Technology, ETH Zurich and 21 more.
Type: Journal Article | Journal: ALTEX | Year: 2016

The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agriculture, food, ecosystems or cosmetics, thus, replacing laboratory animal models used currently. Thirty-six experts from academia, industry and regulatory bodies present here the results of an intensive workshop (held in June 2015, Berlin, Germany). They review the status quo of microphysiological systems available today against industry needs, and assess the broad variety of approaches with fit-for-purpose potential in the drug development cycle. Feasible technical solutions to reach the next levels of human biology in vitro are proposed. Furthermore, key organ-on-a-chip case studies, as well as various national and international programs are highlighted. Finally, a roadmap into the future is outlined, to allow for more predictive and regulatory-accepted substance testing on a global scale.


Hinsenkamp M.,Brussels University | Muylle L.,University of Antwerp | Muylle L.,Federal Agency for Medicines and Health Products | Eastlund T.,University of New Mexico | And 3 more authors.
International Orthopaedics | Year: 2012

Purpose: The use of bone and connective tissue allografts has grown rapidly and surpassed the use of autografts in many countries. Being of human origin, bone and tendon allografts carry the risk of disease transmission and complications have been reported. As part of the Project NOTIFY led by the World Health Organisation, an effort to improve recognition, reporting, tracking and investigation of adverse outcomes of allografts was initiated, achieving a comprehensive review of associated disease transmission and failures. Those involving the use of musculoskeletal allografts are reported here. A major objective is to involve orthopaedic surgeons in the improvement of the safe use of the musculoskeletal allografts. Methods: We reviewed the medical literature, requested reports from surgeons in selected professional organisations and informally surveyed tissue bank organisations and selected tissue bank professionals to discover reported and unreported cases of adverse outcomes. We analysed each case to decide the likelihood that the complication was truly allograft related. Results: The efficiency of the procedures involved in bone banking and bone and tendon allograft has improved significantly during the last three decades. The evolution of the incidence of reported adverse reactions and events reflects positively on the safety of transplanted tissues. Cases of bacterial and viral transmission by bone and tendon allografts occurred mainly with those that contained viable cells, were not processed to remove cells, or were not disinfected or sterilised. We documented cases of transmission of human immunodeficiency virus (HIV), hepatitis C virus (HCV), human T-lymphotropic virus (HTLV), unspecified hepatitis, tuberculosis and other bacteria. Reporting of these adverse outcomes has led to corrective actions and has significantly improved the safety of allograft use. However, it is probable that not all cases have been reported and investigated. Conclusions: Considering the high quality standards achieved in many countries, the best approach for further improvement in the safety of allografts is through a systematic reporting of all serious adverse reactions and events in the context of a global biovigilance programme. © 2011 Springer-Verlag.


Sacre P.-Y.,Scientific Institute of Public Health | Sacre P.-Y.,University of Liège | Deconinck E.,Scientific Institute of Public Health | Daszykowski M.,University of Silesia | And 5 more authors.
Analytica Chimica Acta | Year: 2011

Most of the counterfeit medicines are manufactured in non good manufacturing practices (GMP) conditions by uncontrolled or street laboratories. Their chemical composition and purity of raw materials may, therefore, change in the course of time. The public health problem of counterfeit drugs is mostly due to this qualitative and quantitative variability in their formulation and impurity profiles.In this study, impurity profiles were treated like fingerprints representing the quality of the samples. A total of 73 samples of counterfeit and imitations of Viagra ® and 44 samples of counterfeit and imitations of Cialis ® were analysed on a HPLC-UV system. A clear distinction has been obtained between genuine and illegal tablets by the mean of a discriminant partial least squares analysis of the log transformed chromatograms. Following exploratory analysis of the data, two classification algorithms were applied and compared. In our study, the k-nearest neighbour classifier offered the best performance in terms of correct classification rate obtained with cross-validation and during external validation. For Viagra ®, both cross-validation and external validation sets returned a 100% correct classification rate. For Cialis ® 92.3% and 100% correct classification rates were obtained from cross-validation and external validation, respectively. © 2011 Elsevier B.V.


Pauwels E.,Ghent University | Claeys D.,Ghent University | Claeys D.,Federal Agency for Medicines and Health Products | Martins J.C.,Ghent University | And 4 more authors.
RSC Advances | Year: 2013

Structural analysis of modified DNA with NMR is becoming ever more difficult with increasingly complex compounds under scrutiny for use in medical diagnosis, therapeutics, material science and chemical synthesis. To facilitate this process, we developed a molecular modeling approach to predict proton chemical shifts in sufficient agreement with experimental NMR measurements to guide structure elucidation. It relies on a QM/MM partitioning scheme and first principle calculations to predict the spatial structure and calculate corresponding proton chemical shifts. It is shown that molecular dynamics simulations that take into account solvent and temperature effects properly are of utmost importance to sample the conformational space sufficiently. The proposed computational procedure is applicable to modified oligonucleotides and DNA, attaining a mean error for the proton chemical shifts of less than 0.2 ppm. Here, it is applied on the Drew-Dickerson d(CGCGAATTCGCG)2 dodecamer as a benchmark system and the mispair-aligned N3T-ethyl-N 3T cross-linked d(CGAAAT*TTTCG)2 undecamer, illustrating its use as computational tool to assist in structure elucidation. For the proton chemical shifts in the cross-linked system our methodology yields a strikingly superior description, surpassing the predictive power of (semi-)empirical methods. In addition, our methodology is the only one available to make an accurate prediction for the protons in the actual cross-link. To the best of our knowledge, this is the first computational study that attempts to determine the chemical shifts of oligonucleotides of this size and at this level of complexity. This journal is © 2013 The Royal Society of Chemistry.


Sacre P.-Y.,Scientific Institute of Public Health | Sacre P.-Y.,University of Liège | Deconinck E.,Scientific Institute of Public Health | Saerens L.,Ghent University | And 6 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

During the past years, pharmaceutical counterfeiting was mainly a problem of developing countries with weak enforcement and inspection programs. However, Europe and North America are more and more confronted with the counterfeiting problem. During this study, 26 counterfeits and imitations of Viagra ® tablets and 8 genuine tablets of Viagra ® were analysed by Raman microspectroscopy imaging. After unfolding the data, three maps are combined per sample and a first PCA is realised on these data. Then, the first principal components of each sample are assembled. The exploratory and classification analysis are performed on that matrix. PCA was applied as exploratory analysis tool on different spectral ranges to detect counterfeit medicines based on the full spectra (200-1800cm -1), the presence of lactose (830-880cm -1) and the spatial distribution of sildenafil (1200-1290cm -1) inside the tablet. After the exploratory analysis, three different classification algorithms were applied on the full spectra dataset: linear discriminant analysis, k-nearest neighbour and soft independent modelling of class analogy. PCA analysis of the 830-880cm -1 spectral region discriminated genuine samples while the multivariate analysis of the spectral region between 1200cm -1 and 1290cm -1 returns no satisfactory results. A good discrimination of genuine samples was obtained with multivariate analysis of the full spectra region (200-1800cm -1). Application of the k-NN and SIMCA algorithm returned 100% correct classification during both internal and external validation. © 2011 Elsevier B.V.


Sacre P.-Y.,Scientific Institute of Public Health | Sacre P.-Y.,University of Liège | Deconinck E.,Scientific Institute of Public Health | De Beer T.,Ghent University | And 5 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2010

During this study, Fourier transform infrared spectroscopy (FT-IR), near infrared spectroscopy (NIR) and Raman spectroscopy were applied to 55 samples of counterfeit and imitations of Viagra® and 39 samples of counterfeit and imitations of Cialis®. The aim of the study was to investigate which of these techniques and associations of them were the best for discriminating genuine from counterfeit and imitation samples. Only the regions between 1800-400cm-1 and 7000-4000cm-1 were used for FT-IR and NIR spectroscopy respectively. Partial least square analysis has been used to allow the detection of counterfeit and imitation tablets. It is shown that for the Viagra® samples, the best results were provided by a combination of FT-IR and NIR spectroscopy. On the other hand, the best results for the Cialis® samples were provided by the combination of NIR and Raman spectroscopy (1400-1190cm-1). These techniques not only permitted a clear discrimination between genuine and counterfeit or imitation samples but also the distinction of clusters among illegal samples. This might be interesting for forensic investigations by authorities. © 2010 Elsevier B.V.


de Beer J.O.,Scientific Institute of Public Health | Naert C.,Federal Agency for Medicines and Health Products | Deconinck E.,Scientific Institute of Public Health
Accreditation and Quality Assurance | Year: 2012

Knowledge of the response function (y = f(x)) is essential in the validation of quantitative analysis methods as it describes the mathematical relationship between measurable responses and the concentrations or quantities of the analyte in the sample within a suitable range. The most common response function used is a straight line obtained by ordinary least squares (OLS) regression. Suitability of calibration lines obtained by OLS regression might be verified by calculation of a quality coefficient (QC mean). Mathematical modelling performed previously showed that with respect to critical limit values for g, which controls the symmetry of the prediction interval of the abscissa value obtained from the confidence intervals around the OLS calibration curve, a corresponding quality coefficient value exists as a quality performance parameter which is related to the spread of the abscissa values around their mean. In this paper, new mathematical models are developed to demonstrate to which extend also the number n of calibration points (x i,y i) defines the required value for the quality coefficient (QC mean) for different values of g. From these models, it could be established that the attribution of a critical limit value to QC mean as a performance parameter for straight line calibration cannot be arbitrary chosen but has to rely on the mathematical model relating QC mean, the g-value, the number n of calibration points and the spread of the x i-values around their mean. Practical measures for analysts are provided which tend to lower the g-value of straight calibration lines beneath critical values and enable to improve the quality of the calibration line applied for analysis, as demonstrated in an elaborated example. © 2012 Springer-Verlag.

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