Tregunno P.M.,Medicines and Healthcare Products Regulatory Agency MHRA |
Fink D.B.,Danish Health and Medicines Authority DHMA |
Fernandez-Fernandez C.,Agencia Espanola de Medicamentos y Productos Sanitarios AEMPS |
Lazaro-Bengoa E.,Agencia Espanola de Medicamentos y Productos Sanitarios AEMPS |
And 2 more authors.
Drug Safety | Year: 2014
Background: Individual case reports of suspected harm from medicines are fundamental for signal detection in postmarketing surveillance. Their effective analysis requires reliable data and one challenge is report duplication. These are multiple unlinked records describing the same suspected adverse drug reaction (ADR) in a particular patient. They distort statistical screening and can mislead clinical assessment. Many organisations rely on rule-based detection, but probabilistic record matching is an alternative. Objectives: The aim of this study was to evaluate probabilistic record matching for duplicate detection, and to characterise the main sources of duplicate reports within each data set. Research Design: vigiMatch™, a published probabilistic record matching algorithm, was applied to the WHO global individual case safety reports database, VigiBase®, for reports submitted between 2000 and 2010. Reported drugs, ADRs, patient age, sex, country of origin, and date of onset were considered in the matching. Suspected duplicates for the UK, Denmark, and Spain were reviewed and classified by the respective national centre. This included evaluation to determine whether confirmed duplicates had already been identified by in-house, rule-based screening. Furthermore, each confirmed duplicate was classified with respect to the likely source of duplication. Measures: For each country, the proportions of suspected duplicates classified as confirmed duplicates, likely duplicates, otherwise related, and unrelated were obtained. The proportions of confirmed or likely duplicates that were not previously known by the national organisation were determined, and variations in the rates of suspected duplicates across subsets of reports were characterised. Results: Overall, 2.5 % of the reports with sufficient information to be evaluated by vigiMatch were classified as suspected duplicates. The rates for the three countries considered in this study were 1.4 % (UK), 1.0 % (Denmark), and 0.7 % (Spain). Higher rates of suspected duplicates were observed for literature reports (11 %) and reports with fatal outcome (5 %), whereas a lower rate was observed for reports from consumers and non-health professionals (0.5 %). The predictive value for confirmed or likely duplicates among reports flagged as suspected duplicates by vigiMatch ranged from 86 % for the UK, to 64 % for Denmark and 33 % for Spain. The proportions of confirmed duplicates that were previously unknown to national centres ranged from 89 % for Spain, to 60 % for the UK and 38 % for Denmark, despite in-house duplicate detection processes in routine use. The proportion of unrelated cases among suspected duplicates were below 10 % for each national centre in the study. Conclusions: Probabilistic record matching, as implemented in vigiMatch, achieved good predictive value for confirmed or likely duplicates in each data source. Most of the false positives corresponded to otherwise related reports; less than 10 % were altogether unrelated. A substantial proportion of the correctly identified duplicates had not previously been detected by national centre activity. On one hand, vigiMatch highlighted duplicates that had been missed by rule-based methods, and on the other hand its lower total number of suspected duplicates to review improved the accuracy of manual review. © 2014 UK Crown: Medicines and Healthcare Products Regulatory Agency (DH); Crown Copyright.
Pani L.,Italian Medicines Agency AIFA |
Pecorelli S.,Italian Medicines Agency AIFA |
Rosano G.,Italian Medicines Agency AIFA |
Rosano G.,St George's, University of London |
And 7 more authors.
European Journal of Heart Failure | Year: 2015
A workshop was organized by the Agenzia Italiana del Farmaco (AIFA) to discuss unmet needs and ways forward in the development of medicines in heart failure, their rationale, and cost-effective use. An integrated, multidisciplinary approach, including patients' needs and perspectives, was advocated by all the participants as the way to the most effective treatment regimens. More work is needed for reaching consensus on clinical and functional endpoints, for validating patient reported outcomes and measurements of well-being. Similarly, the integration into the clinical programmes of the health technology assessment/payers perspective, in particular, the evaluation of 'real-life' treatment effectiveness and of health as a value, would help in shifting the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole health care regimen. Through this kind of workshop, AIFA is trying to build a template for meetings devoted to debate unmet needs with all stakeholders towards tentative road maps for the future. © 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.
Martinalbo J.,European Medicines Agency EMA |
Bowen D.,European Medicines Agency EMA |
Camarero J.,Spanish Agency for Medicines and Healthcare Products AEMPS |
Chapelin M.,European Medicines Agency EMA |
And 9 more authors.
Annals of Oncology | Year: 2016
Patient access to new cancer drugs in the EU involves centralised licensing decisions by regulators as well as reimbursement recommendations in the context of national healthcare systems. Differences in assessment criteria and evidence requirements may result in divergent decisions at central and national levels, ultimately compromising effective access to patients. Early access decisions are particularly challenging due to the limited clinical evidence available to conclude on the benefit-risk and relative (cost-) effectiveness of new high-priced cancer drugs. We describe mechanisms to accelerate approval of promising anticancer drugs that fulfil an unmet medical need, review the experience from the European Medicines Agency, compare timelines and outcomes of reimbursement decisions in major EU markets, and discuss shortcomings of the current system, ongoing initiatives, and future steps to facilitate effective early access. © The Author 2015.
Ehmann F.,European Medicines Agency |
Caneva L.,European Medicines Agency |
Prasad K.,Pharmacogenomics Working Party European Medicines Agency EMA |
Prasad K.,Medicines and Healthcare Products Regulatory Agency MHRA |
And 8 more authors.
Pharmacogenomics Journal | Year: 2015
Pharmacogenomics (PGx) has a growing impact on healthcare and constitutes one of the major pillars of personalised medicine. For the purpose of improved individualised drug treatment, there is an increasing effort to develop drugs suitable for specific subpopulations and to incorporate pharmacogenomic drug labels in existing and novel medicines. Here, we review the pharmacogenomic drug labels of all 517 medicinal products centrally approved in the European Union (EU) since the establishment of the European Medicines Agency in 1995. We identified all pharmacogenomic-related information mentioned in the product labels and classified it according to its main effect and function on drug treatment, that is, metabolism, transport and pharmacodynamics, and according to the place of the respective section of the Summary of Product Characteristics (SmPC). The labels are preferentially present in drugs having antineoplastic properties. We find that the number of drugs with pharmacogenomic labels in EU increases now steadily and that it will be an important task for the future to refine the legislation on how this information should be utilised for improvement of drug therapy.
Shepard T.,Medicines and Healthcare Products Regulatory Agency MHRA |
Scott G.,Takeda Development Center Europe |
Cole S.,Medicines and Healthcare Products Regulatory Agency MHRA |
Nordmark A.,Swedish Medical Products Agency MPA |
Bouzom F.,Technology Servier
CPT: Pharmacometrics and Systems Pharmacology | Year: 2015
Under the remit of the Ministerial Industry Strategy Group (MISG), the Association of the British Pharmaceutical Industry (ABPI) and Medicines and Healthcare products Regulatory Agency (MHRA) hosted a meeting to explore physiologically based pharmacokinetic modeling and simulation, focusing on the clinical component of regulatory applications. The meeting took place on 30 June 2014 with international representatives from industry, academia, and regulatory agencies. Discussion topics were selected to be complementary to those discussed at an earlier US Food and Drug Administration (FDA) meeting. This report summarizes the meeting outcomes, focusing on the European regulatory perspective. © 2015 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.
Hemmings R.,Medicines and Healthcare Products Regulatory Agency MHRA
Journal of Biopharmaceutical Statistics | Year: 2014
Whether confirmatory or exploratory in nature, the investigation of subgroups poses statistical and interpretational challenges, yet these investigations can have important consequences for product licensing, labeling, reimbursement, and prescribing decisions. This article provides a high-level, nontechnical summary of key statistical issues in the analysis of subgroups, with a focus on the regulatory context in which drug development and licensing decisions are made. References to specific aspects of regulatory processes are based on the system in Europe, though it is hoped that the principles outlined can be generally applied to other regulatory regions. This article challenges the common assumption that a clinical trial population should be assumed to be homogeneous, with homogeneous response to treatment, and asks whether commonly employed strategies for handling and identifying potential heterogeneity are sufficient. Investigations into subgroups are unavoidable, yet subgroup analyses suffer from fundamental complications and limitations of which those planning and interpreting clinical trials must be aware. Some areas for further methodological work and an improved methodological framework for the conduct of exploratory subgroup analyses are discussed. Above all, the need for an integrated scientific approach is highlighted. © 2014 Crown copyright.
Dissanayake S.,Medicines and Healthcare Products Regulatory Agency MHRA
British Journal of Clinical Pharmacology | Year: 2010
Background: Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed. Aims: To critically review methods used to overcome confounding biases in bioequivalence studies of 'endogenous' drugs. Methods: A literature search of the EMBASE and PubMed databases was performed. Results: The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of 'substance-deficient' populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra-therapeutic drug doses. Conclusions: On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so-called 'endogenous drugs', are described. The dual stable isotope method, which could be used in a specific context, is also discussed. © 2010 The British Pharmacological Society.
Davis B.,Medicines and Healthcare Products Regulatory Agency MHRA |
Southworth H.,Data Clarity Consulting Ltd
Therapeutic Innovation and Regulatory Science | Year: 2016
Background: Monitoring safety in clinical trials by regulatory authorities and sponsors involves the clinical review, often subjectively, of large data sets of different types of safety information which may require considerable resources. Methods: This study investigated a means of statistically guided clinical review of safety data provided in the Cumulative Table of Serious Adverse Events of a Development Safety Update Report (DSUR). A simple statistical approach that treats every adverse event as independent of all others and uses a reference prior, which avoids infinite estimates of relative risk but does not unduly influence posterior inferences, was used with fixed rules of relative risk to identify a serious adverse event preferred term as a potential risk. Results: This simple model, using cumulative serious adverse event (SAE) data from 5 DSURs, identified a small group of potential risks that included some not reported by the sponsor as well as most of those reported by the sponsor in the DSUR Summary of Important Risks. Conclusions: The method provides a systematic and objective approach to analysis of cumulative SAE data that could help to identify potential risks that need further investigation by a regulatory authority or sponsor. © 2015, The Author(s) 2015.
Jones D.R.,Medicines and Healthcare Products Regulatory Agency MHRA |
Inhalation Toxicology | Year: 2013
Regulatory guidelines are intended to provide recommendations on ways to achieve greater harmonization in the interpretation and application of technical procedures and requirements for product registration in order to reduce or obviate replication of the testing carried out during the research and development of new products. The objectives of such harmonization are more economical use of human, animal and material resources; the elimination of unnecessary delay in the global development and availability of new products while maintaining safeguards on quality, safety and efficacy; and the fulfillment of regulatory obligations to protect public health. © 2013 Informa UK Ltd All rights reserved.
Jones D.R.,Medicines and Healthcare products Regulatory Agency MHRA |
Mcblane J.W.,Medicines and Healthcare products Regulatory Agency MHRA |
Mcnaughton G.,Medicines and Healthcare products Regulatory Agency MHRA |
Rajakumaraswamy N.,Medicines and Healthcare products Regulatory Agency MHRA |
Wydenbach K.,Medicines and Healthcare products Regulatory Agency MHRA
British Journal of Clinical Pharmacology | Year: 2013
The safety of trial subjects is the tenet that guides the regulatory assessment of a Clinical Trial Authorization application and applies equally to trials involving small molecules and those with biological/biotechnological products, including Advanced Therapy Medicinal Products. The objective of a regulator is to ensure that the potential risk faced by a trial subject is outweighed by the potential benefit to them from taking part in the trial. The focus of the application review is to assess whether risks have been identified and appropriate steps taken to alleviate these as much as possible. Other factors are also taken into account during a review, such as regulatory requirements, and emerging non-clinical and clinical data from other trials on the same or similar products. This paper examines the regulatory review process of a Clinical Trial Authorization application from the perspectives of Quality, Non-Clinical and Clinical Regulatory Assessors at the Medicines and Healthcare products Regulatory Agency. It should be noted that each perspective has highlighted specific issues from their individual competence and that these can be different between the disciplines. © 2012 The British Pharmacological Society. This article A regulatory perspective of clinical trial applications for biological products with particular emphasis on Advanced Therapy Medicinal Products (ATMPs) was written by David R. Jones, James W. McBlane, Graham McNaughton, Nishanthan Rajakumaraswamy & Kirsty Wydenbach of Medicines and Healthcare Products Regulatory Agency (MHRA). It is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.