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Hemmings R.,Medicines and Healthcare Products Regulatory Agency MHRA
Journal of Biopharmaceutical Statistics

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. Source

Dissanayake S.,Medicines and Healthcare Products Regulatory Agency MHRA
British Journal of Clinical Pharmacology

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. Source

Pani L.,Italian Medicines Agency AIFA | Pecorelli S.,Italian Medicines Agency AIFA | Rosano G.,Italian Medicines Agency AIFA | Rosano G.,St Georges, University of London | And 6 more authors.
European Journal of Heart Failure

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. Source

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

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. Source

Davis B.,Medicines and Healthcare Products Regulatory Agency MHRA | Southworth H.,Data Clarity Consulting Ltd
Therapeutic Innovation and Regulatory Science

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. Source

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