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Pignatti F.,European Medicines Agency EMA | Jonsson B.,Lakemedelsverket | Blumenthal G.,U.S. Food and Drug Administration | Justice R.,U.S. Food and Drug Administration
Molecular Oncology | Year: 2015

Drug licensing and approval decisions involve the balancing of benefits against the risks (harms) in the presence of uncertainty. Typically, the benefits are estimated from primary efficacy endpoints from confirmatory (phase III) clinical trials although exceptions where promising early data from single-arm studies have led to accelerated approvals are not uncommon, particularly for cancer drugs.The challenge for regulators is to balance early evidence of efficacy that might support approval versus the need to establish clinical benefit based on conclusive evidence. Targeted agents offer the promise that knowledge about the mechanism of the disease will help identify patients with tumors likely to respond, resulting in higher efficacy and less toxicity, and earlier regulatory decisions based on convincing evidence of clinical benefit.In this paper, we describe methods and examples of benefit-risk assessment of targeted drugs, recent initiatives from EMA and FDA on improving communication about benefits and risks, and discuss future steps. © 2014.


Freire-Moran L.,European Medicines Agency EMA | Aronsson B.,European Medicines Agency EMA | Manz C.,Duke University | Gyssens I.C.,Radboud University Nijmegen | And 5 more authors.
Drug Resistance Updates | Year: 2011

Two commercial databases (Pharmaprojects and Adis Insight R&D) were queried for antibacterial agents in clinical development. Particular attention was given to antibacterial agents for systemic administration. For each agent, reviewers were requested to indicate whether its spectrum of activity covered a set of selected multidrug-resistant bacteria, and whether it had a new mechanism of action or a new target. In addition, PubMed was searched for antibacterial agents in development that appeared in review articles. Out of 90 agents that were considered to fulfil the inclusion criteria for the analysis, 66 were new active substances. Fifteen of these could be systemically administered and were assessed as acting via a new or possibly new mechanism of action or on a new or possibly new target. Out of these, 12 agents were assessed as having documented in vitro activity against antibiotic-resistant Gram-positive bacteria and only four had documented in vitro activity against antibiotic-resistant Gram-negative bacteria. Of these four, two acted on new or possibly new targets and, crucially, none acted via new mechanisms of action. There is an urgent need to address the lack of effective treatments to meet the increasing public health burden caused by multidrug-resistant bacteria, in particular against Gram-negative bacteria. © 2011 Elsevier Ltd. All Rights Reserved.


Koenig F.,Medical University of Vienna | Slattery J.,European Medicines Agency EMA | Groves T.,BMJ | Lang T.,AGES Austrian Agency for Health and Food Safety | And 4 more authors.
Biometrical Journal | Year: 2015

In recent months one of the most controversially discussed topics among regulatory agencies, the pharmaceutical industry, journal editors, and academia has been the sharing of patient-level clinical trial data. Several projects have been started such as the European Medicines Agencýs (EMA) "proactive publication of clinical trial data", the BMJ open data campaign, or the AllTrials initiative. The executive director of the EMA, Dr. Guido Rasi, has recently announced that clinical trial data on patient level will be published from 2014 onwards (although it has since been delayed). The EMA draft policy on proactive access to clinical trial data was published at the end of June 2013 and open for public consultation until the end of September 2013. These initiatives will change the landscape of drug development and publication of medical research. They provide unprecedented opportunities for research and research synthesis, but pose new challenges for regulatory authorities, sponsors, scientific journals, and the public. Besides these general aspects, data sharing also entails intricate biostatistical questions such as problems of multiplicity. An important issue in this respect is the interpretation of multiple statistical analyses, both prospective and retrospective. Expertise in biostatistics is needed to assess the interpretation of such multiple analyses, for example, in the context of regulatory decision-making by optimizing procedural guidance and sophisticated analysis methods. © 2014 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Davies E.H.,University College London | Saint Raymond A.,European Medicines Agency EMA
European Journal of Clinical Pharmacology | Year: 2010

Purpose: To examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA). Methods: Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis. Results: Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products. Conclusions: The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain. © 2010 Springer-Verlag.


Diez O.,European Medicines Agency EMA | Silva A.,Technical University of Madrid
Quality and Reliability Engineering International | Year: 2014

With the increasing utilisation of Internet services and cloud computing by many organisations (both private and public), it is clear that computing is becoming the fifth utility (along with water, electricity, telephony and gas). These technologies are used for almost all types of systems, and critical systems are now no exception. Even if critical systems appear not to rely directly on cloud services, there may be hidden interdependencies that could affect their resilience. This paper investigates the uses of cloud computing in relation to critical systems and how this affects their resilience, initially comparing it with existing models and frameworks. Some examples are presented together with the associated risks. A framework is introduced for analysing the dependability and resilience of a system that relies on cloud services and how to improve them. As part of the framework, the concepts of micro and macro dependability are introduced to explain the internal and external dependability on services supplied by an external cloud. A pharmacovigilance model system has been used for framework validation. Copyright © 2014 John Wiley & Sons, Ltd. Copyright © 2014 John Wiley & Sons, Ltd.


Granstrom M.,Karolinska University Hospital | Granstrom M.,Paediatric Committee of the European Medicines Agency EMA | Granstrom M.,European Medicines Agency EMA | Voordouw A.C.G.,European Medicines Agency EMA
Vaccine | Year: 2011

Current trivalent inactivated influenza vaccines (TIV) for seasonal use have all been licensed in the EU based on serological data only. European Medicines Agency (EMA) guidelines for development of influenza vaccines and acceptance criteria are in place for adults but not for children. The Paediatric Committee initiated a review of the literature on influenza vaccines for children, which led to the conclusion that for new influenza vaccines the Paediatric Investigation Plan (PIP) will need to include an efficacy trial. A review of the serological assays raised questions on the relevance of the current assays for children and on the methodological differences in the performance of the neutralisation test. The basis for the current correlate for immune protection is been discussed and the role of antibodies to the neuraminidase for protection against disease has increasingly been recognised. These considerations, together with the experiences gathered during the pandemic, resulted in an ongoing revision of the EMA guidelines for influenza vaccines to be replaced by a single guideline with the aim of having better characterised influenza vaccines that will also address the needs of children. © 2011 Elsevier Ltd.


Diez O.,European Medicines Agency EMA | Silva A.,Technical University of Madrid
IEEE Technology and Society Magazine | Year: 2013

Cloud services might provide benefits for public organizations, but governments have been slow to adopt their use. The main indirect benefits of the use of cloud services in public organizations will come from the use of app stores and social media. The first will permit re-use of software and services, mainly when using SaaS and PaaS, permitting rapid deployment of new functionality. The use of social media and collaboration directly with users could permit a new paradigm in the way the public services are used by the public, allowing users to add and manipulate data and even applications that will use the data. In order to accomplish this change successfully it is very important that public bodies work together with providers defining proper standards and services that meet the requirements of public bodies. Amazon GovCloud for the U.S. is one such public cloud service that ensures data do not leave the U.S. and that the service complies with FISMA (The Federal Information Security Management Act of 202) moderated controls.


Isaac M.,European Medicines Agency EMA | Gispen-de Wied C.,Medicines Evaluation Board MEB
European Neuropsychopharmacology | Year: 2015

Our objectives are to describe the procedure for qualification advice and opinion from EU regulators on the use of novel methodologies in drug development, the key stakeholders involved and the evidence requirements for qualification opinion.We present a case study of the request from the Coalition Against Major Disease (CAMD) Consortium of the Critical Path (C-Path) Institute for EU regulators' qualification opinion on the use of low hippocampal volume as a biomarker for population enrichment in clinical trials of novel drugs in Alzheimer's disease (AD). We discuss the main concerns from the regulators, data analysis requests and guidance during the qualification.EU regulators concluded that low hippocampal volume, measured by vMRI and considered as a dichotomized variable (low volume or not), appears to help enriching recruitment into clinical trials aimed at studying drugs that potentially slow the progression of the pre-dementia stage of AD.The biomarker qualification procedure is a dynamic process in which pharmaceutical companies and research consortia can submit further data to update the qualifications and improve the predictive value of the biomarkers. © 2015 Elsevier B.V. and ECNP.


Kozarewicz P.,European Medicines Agency EMA
International Journal of Pharmaceutics | Year: 2014

Current knowledge about the age-appropriateness of different dosage forms is still fragmented or limited. Applicants are asked to demonstrate that the target age group(s) can manage the dosage form or propose an alternative strategy. However, questions remain about how far the applicant must go and what percentage of patients must find the strategy 'acceptable'. The aim of this overview is to provide an update on current thinking and understanding of the problem, and discuss issues relating to the acceptability testing. This overview should be considered as means to start a wider discussion which hopefully will result in a harmonised, globally acceptable approach for confirmation of the acceptability in the future. © 2014 Elsevier B.V.


Isaac M.,European Medicines Agency EMA | Vamvakas S.,European Medicines Agency EMA | Abadie E.,European Medicines Agency EMA | Jonsson B.,European Medicines Agency EMA | And 2 more authors.
European Neuropsychopharmacology | Year: 2011

The European Medicines Agency (EMA) in London is responsible for the Regulatory review of new medicinal products for Marketing Authorisation, through which pharmaceutical companies may obtain first Marketing Authorisation and subsequent Variations valid throughout the EU and EFTA.The qualification opinion of novel methodologies is a new procedure where applicants can obtain scientific advice on new methodologies for regulatory clinical trials of efficacy of new compounds. It will help benefit/risk assessment of the CHMP.The definition of prodromal AD is acceptable. The "Dubois Criteria" as criteria to define the population must be validated in full at the time of the submission of the dossiers.Including a positive CSF biomarker profile is considered predictive for the evaluation of the AD-dementia type. However, although high CSF tau and low CSF Aβ42 are predictive of Alzheimer's disease, the criterion "positive CSF tau/Aβ42 ratio" is not well defined.The qualification of biomarkers in the pre-dementia stage of Alzheimer's disease will allow better inclusion criteria of patients in pre-dementia trials in which the benefit/risk is higher for treatment with these novel compounds. © 2011 Elsevier B.V. and ECNP.

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