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Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016.

ABSTRACT: AIMS:To provide insights into the clinical development pathway for fixed-dose combinations (FDCs), to consider strategies, and to elucidate the path to approval by assessing the body of evidence, as summarized in the European Public Assessment Reports. METHODS:The main resource was the European Public Assessment Reports for 36 FDCs, which included 239 clinical trials with 157 514 patients. The analyses focused on how prior knowledge of the active substances or combination, use of pharmacokinetic-pharmacodynamic modelling, and clinical trial design choice impact the size and strategy of the clinical development programme. RESULTS:FDC products primarily comprised 2 previously approved components (21/36, 71%) and had only 1 approved combination (21/36, 71%). Utilizing previously approved active substances resulted in fewer clinical trials, arms and patients, but FDC doses studied in the clinical development programme. Furthermore, dose-finding trials were performed for less than half of FDCs consisting of 2 previously approved active substances. The standard approach to demonstrate contribution of active substances was through a factorial or single combination study. Finally, the use of pharmacokinetic modelling showed a significant decrease in the number of FDC doses studied. CONCLUSIONS:The field of FDCs seems to be on the rise, utilizing new molecular entities, prior knowledge and re-profiling drugs. However, a way to move FDC development forward might be through new regulatory and scientific paradigms, in which it is encouraged to utilize model-based approaches to develop FDCs with multiple dose levels and dose ratios for exposure-based treatment that will enable personalization.

SUBMITTER: Nohr-Nielsen A

PROVIDER: S-EPMC6624404 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016.

Nøhr-Nielsen Asbjørn A De Bruin Marie Louise ML Thomsen Mikael M Pipper Christian Bressen CB Lange Theis T Bjerrum Ole Jannik OJ Lund Trine Meldgaard TM

British journal of clinical pharmacology 20190617 8

<h4>Aims</h4>To provide insights into the clinical development pathway for fixed-dose combinations (FDCs), to consider strategies, and to elucidate the path to approval by assessing the body of evidence, as summarized in the European Public Assessment Reports.<h4>Methods</h4>The main resource was the European Public Assessment Reports for 36 FDCs, which included 239 clinical trials with 157 514 patients. The analyses focused on how prior knowledge of the active substances or combination, use of ...[more]

PMID: 31077427

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Project description:BackgroundThere is an increasing global interest in selection processes for candidates to surgical training. The aim of the present study is to compare selection processes to specialist surgeon training in the European Union (EU). A secondary goal is to provide guidance for evidence-based methods by a proposed minimum standard that would align countries within the EU.MethodsPublications and grey literature describing selection strategies were sought. Correspondence with Union Européenne des Médecins Specialists (UEMS) Section of Surgery delegates was undertaken to solicit current information on national selection processes. Content analysis of 13 semi-structured interviews with experienced Swedish surgeons on the selection process. Two field trips to Ireland, a country with a centralized selection process were conducted. Based on collated information typical cases of selection in a centralized and decentralized setting, Ireland and Sweden, are described and compared.ResultsA multitude of methods for selection to surgical training programs were documented in the 27 investigated countries, ranging from locally run processes with unstructured interviews to national systems for selection of trainees with elaborate structured interviews, and non-technical and technical skills assessments. Associated with the difference between centralized and decentralized selection systems is whether surgical training is primarily governed by an employment or educational logic. Ireland had the most centralized and elaborate system, conducting a double selection process using evidence-based methods along an educational logic. On the opposite end of the scale Sweden has a decentralized, local selection process with a paucity of evidence-based methods, no national guidelines and operates along an employment logic, and Spain that rely solely on examination tests to rank candidates.ConclusionThe studied European countries all have different processes for selection of surgical trainees and the use of evidence-based methods for selection is variable despite similar educational systems. Selection in decentralized systems is currently often conducted non-transparent and subjectively. A suggested improvement towards an evidence-based framework for selection applicable in centralized and decentralized systems as well as educational and employer logics is suggested.

Project description:BACKGROUND:Tuberculosis (TB) control programmes rely heavily on laboratories to support both clinical care and public health. Qualified personnel with adequate technical and managerial skills comprise an integral component of any quality assured laboratory. Training a new generation of TB laboratory specialists was identified as a critical priority in the European Union /European Economic Area (EU/EEA). A tailored training programme for TB reference laboratory professionals was developed and implemented within the European Reference Laboratory Network for Tuberculosis to increase the pool of technical experts available to step into leadership roles in the TB laboratory community. Three cohorts of selected laboratory specialists participated in a series of trainings from 2009 to 2016. METHODS:We conducted an evaluation of the training programme using a structured questionnaire administered via the EUSurvey website, with the aim of documenting the benefits and contribution as well as suggesting improvements and future direction of the programme. All graduated participants and all current ERLTB-Net members were invited to participate in the online survey and descriptive quantitative analysis was performed. RESULTS:The evaluation found significant benefits for both the participants and the participants' institutions, with improvements being reported in laboratory practices and management including implementation of new diagnostic techniques and career progression for participants. The training programme differed from other international and European initiatives in a number of important ways; the curriculum is unique in the scope and range of topics covered; the programme targets senior level professionals and future directors; cohorts were limited to 8-10 participants; and the programme involved a number of workshops (5-7) taking place over a two-year period. Relationships and collaborations established between individuals and institutions were valued as an important success of the initiative. Suggestions on how the impact of the programme could be enhanced included equipping participants to perform laboratory assessments in low-resource settings outside the EU, thus bolstering global TB control. CONCLUSION:Based on the findings presented the training programme has proved to be successful in developing leadership, expertise, partnerships and networks to support TB laboratories and has contributed significant benefits to strengthening European National Reference laboratories in the fight against TB.

Project description:ObjectivesThe aim of this study was to assess the current evidence for long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the treatment of COPD.Materials and methodsA systematic literature search of randomized controlled trials published in English up to September 2017 of LABA/LAMA FDCs vs LABA or LAMA or LABA/inhaled corticosteroid (ICS) FDCs in COPD patients was performed using PubMed, Embase, Scopus, and Google Scholar. Outcomes including forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index (TDI) scores, St George's Respiratory Questionnaire (SGRQ) scores, exacerbations, exercise tolerance (endurance time [ET]), inspiratory capacity (IC), and rescue medication use were evaluated.ResultsIn total, 27 studies were included in the review. LABA/LAMA FDCs significantly improved lung function (FEV1) at 12 weeks compared with LABA or LAMA or LABA/ICS. These effects were maintained over time. Significant improvements with LABA/LAMA FDCs vs each evaluated comparator were also observed in TDI and SGRQ scores, even if significant differences between different LABA/LAMA FDCs were detected. Only the LABA/LAMA FDC indacaterol/glycopyrronium has shown superiority vs LAMA and LABA/ICS for reducing exacerbation rates, while olodaterol/tiotropium and indacaterol/glycopyrronium have been shown to improve ET and IC vs the active comparators. Rescue medication use was significantly reduced by LABA/LAMA FDCs vs the evaluated comparators. LABA/LAMA FDCs were safe, with no increase in the risk of adverse events with LABA/LAMA FDCs vs the monocomponents.ConclusionEvidence supporting the efficacy of LABA/LAMA FDCs for COPD is heterogeneous, particularly for TDI and SGRQ scores, exacerbation rates, ET, and IC. So far, indacaterol/glycopyrronium is the LABA/LAMA FDC that has the strongest evidence for superiority vs LABA, LAMA, and LABA/ICS FDCs across the evaluated outcomes. LABA/LAMA FDCs were safe; however, more data should be collected in a real-world setting to confirm their safety.

Dataset Information

Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016.

Publications

Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016.

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