European Union Clinical Trials Directive Research Articles

Study protocol for a phase 1, randomised, double-blind, placebo-controlled study to investigate the safety, tolerability and pharmacokinetics of ascending topical doses of TCP-25 applied to epidermal suction blister wounds in healthy male and female volunteers

IntroductionTCP-25 gel is intended for use in treatment of wound infection and inflammation. Current local therapies for wounds have limited efficacy to prevent infections and there are no wound treatments...

Heterogeneity of national legislation and practice on clinical trials with vulnerable patients based on the EU Clinical Trials Directive by the example of adults permanently incapable of giving informed consent.

In principle, persons wishing to participate in a clinical trial must give informed consent in advance after comprehensive information has been provided. Under certain conditions, it is possible to deviate from this requirement in the European Union (EU) in order to enable the participation of so-called vulnerable persons who are incapable of giving their informed consent. Kuthning et al. [1] have already dealt with general and specific aspects of vulnerable patients and the principle of informed consent in clinical trials. One group of vulnerable persons, for example, are adults temporarily or permanently incapable of giving consent due to their state of health. For a long period of time, no systematic and uniform legal basis for clinical trials existed in the EU as a whole. The Clinical Trials Directive (CTD) [2], adopted in 2001, aimed to change this by harmonizing all legal regulations on clinical trials applicable in the EU, but nevertheless allowing national deviations in implementation into national laws through opening clauses and aspects that were left unregulated. In view of the Clinical Trials Regulation (CTR) [3] which, according to the current status, will with high probability be applied from 2022 on, and which in future will be the legal basis for clinical trials with medicinal products in humans, applied directly in all EU member states, the necessity to take stock of the effects of the CTD was evident.The national deviations with regard to the participation of patients incapable of giving informed consent were investigated qualitatively and quantitatively by means of a systematic analysis of legislation in 16 EU countries and a retrospective database analysis of a European clinical trial registry over a ten-year observation period. Although the analysis initially showed a predominantly homogeneous picture, the differences between the EU member states became apparent in a detailed examination. The database analysis yielded a clear result, since in some countries the majority of clinical trials are carried out. The clearest difference was found between the legal analysis and the results of the evaluated clinical trials concerning adults who are permanently incapable of giving informed consent. A presumed association between the “degree of liberality” of the national law and the frequency of clinical trials conducted in the respective country could not be confirmed. In the past, the selection of countries for conducting a clinical trial was based less on legal requirements and more on experience and financial considerations.

Shotgun Mass Spectrometry-Based Lipid Profiling Identifies and Distinguishes Between Chronic Inflammatory Diseases

Aims: Inflammation impacts several acute and chronic diseases causing localized stress and cell death, releasing tissue-specific lipids into the circulation from inflamed cells and tissues. The plasma lipidome may be expected to reflect the type of inflammation. However, deep lipid profiles of major chronic inflammatory diseases have not been compared. Methods and Results: We compared the plasma lipidomes of patients suffering from two etiologically distinct chronic inflammatory diseases, atherosclerosis-related cardiovascular disease (CVD) including ischemic stroke (IS), and systemic lupus erythematosus (SLE), to each other and to age-matched controls. The controls had never suffered from any of these diseases. Plasma lipidomes were screened by a top-down shotgun MS-based analysis without liquid chromatographic separation. Lipid profiling of 596 lipids based on MS was performed on a cohort of 427 individuals. Machine learning classifiers based on the plasma lipidomes of patients suffering from CVD and SLE allowed clear distinction of these two chronic inflammatory diseases from each other. We demonstrate convincing evidence for the capability of lipidomics to separate the studied chronic and inflammatory diseases from controls based on independent validation test set classification performance (CVD vs control - Sensitivity: 0.90, Specificity: 0.98; IS vs control - Sensitivity: 1.0, Specificity: 1.0; SLE vs control – Sensitivity: 1, Specificity: 0.88) and from each other (SLE vs CVD ‒ Sensitivity: 0.91, Specificity: 1). Preliminary linear discriminant analysis plots using all data clearly separated the clinical groups from each other and from the controls. In addition, CVD severities, as classified into five clinical groups, were partially separable by linear discriminant analysis. Conclusions: Dysregulation of the plasma lipidome is characteristic of chronic inflammatory diseases. Lipid profiling accurately identifies the diseases and in the case of CVD also identifies sub-classes. Dysregulated lipids are partially but not fully counterbalanced by statin treatment. Clinical Trial Registration Details: This study was registered with the Clinical Trials number NCT04786431 Funding Information: This work was supported by PTDC/MED-PAT/29395/2017 financially supported by Fundacao paraKS is CEO and shareholder of of Lipotype GmbH. CL and MG are KS is CEO and shareholder of of Lipotype GmbH. CL and MG are employees of Lipotype GmbH. All other authors declare that they do not have any competing interestsemployees of Lipotype GmbH. All other authors declare that they do not have any competing interests424 a Ciencia e a Tecnologia (FCT), through national funds and co-funded by FEDER under the PT2020 Partnership. ND was a holder of PhD fellowship from the FCT (Ref. N°:SFRH/BD/51877/2012), attributed 10 by Inter-University Doctoral Programme in Ageing and Chronic Disease (PhDOC). LA was a holder of a FCT PhD fellowship (PD/BD/114254/2016), attributed by the ProRegem Doctoral Programme in 2016. Declaration of Interests: KS is CEO and shareholder of of Lipotype GmbH. CL and MG are employees of Lipotype GmbH. All other authors declare that they do not have any competing interests. Ethics Approval Statement: The entire process was approved by the Ethical Review Board of the Faculty of Medicine of the New University of Lisbon and the Ethics Committee for Health of the Centro Hospitalar de Lisboa Ocidental, that includes the Hospital Santa Cruz, the Hospital Egas Moniz and Hospital Sao Francisco Xavier, and the Ethics Committee for Health of the Hospital Fernando Fonseca. All experiments were performed in accordance with the guidelines and regulations including, the Universal Declaration on Bioethics and Human Rights of UNESCO, 2005; The Charter of Fundamental rights of the EU, 2012; Ethical principles for medical research involving human subjects - Declaration of Helsinki, 2013; EU Regulation 2016/679 and Good Clinical Practice guidelines (Directive 2001/20/EC) and EU Clinical Trials Directive (2005/28/EC). Moreover, they complied with national legislations for the scientific use of human biological samples (Law No 12/2005 and No 131/2014).

Effects of EU harmonization policies on national public supervision of clinical trials: A dynamic cycle of institutional change and institutional work

BackgroundThe EU Clinical Trials Directive (EUCTD) and the EU Clinical Trials Regulation aim to harmonize good clinical practice (GCP) of clinical trials across Member States. Using the Netherlands as a case study, this paper analyzes how endeavours to implement the EUCTD set in motion a dynamic process of institutional change and institutional work. This process lead to substantial differences between policy and actual practice; therefore, it is important to learn more about the implementation of harmonization policies. MethodsRelevant documents, such as legal texts and previous research, were analyzed. Interviews were conducted with stakeholders in clinical trials and inspectors from (inter)national supervisory bodies (n=33), and Dutch Health Care Inspectorate inspections were observed (n=4). ResultsDutch legislators’ efforts to implement the EUCTD created a new level of governance in an already multilevel legislative framework. Institutional layering caused a complex and fragmented organizational structure in public supervision, leading to difficulties in achieving GCP. This instigated institutional work by actors, which set in motion further incremental institutional change, principally drift and conversion. ConclusionsHarmonization processes can create dynamic cycles between institutional change and institutional work, leading to significant divergence from the intended effects of legislation. If legislation intended to strengthen harmonization is not carefully implemented, it can become counterproductive to its aims.

Just a simple observational follow-up study?

Observational cohort studies are usually assumed to be simpler to set up and deliver than a RCT. But what happens when the cohort previously took part in a randomised CTIMP? Its anything but simple. We describe our experience of setting up an observational cohort study of patients who took part in the IVAN trial. IVAN was a multi-centre RCT comparing bevacizumab with the standard treatment of ranibizumab for the treatment of wet age-related macular degeneration. Participants exited the trial on average 5 years ago, and if they continued to be treated under the NHS would have received ranibizumab. For this follow-up study no treatment is planned, data will be collected on treatment since the end of the trial, most recent visual acuity and imaging of the eye. Visual acuity and imaging data will be collected at a dedicated research visit if participants are willing to attend or from routine sources. Challenges include 1. MHRA consider this follow-up study falls under the remit of the EU Clinical Trials Directive; i.e. that is a CTIMP, requiring amongst other things SAE reporting. 2. The trial population were elderly; a large proportion is likely to be too infirm to attend or have died. They may also have moved? How do we maximise the number of participants included to make sure the results are meaningful? 3. Some sites had low recruitment so the resources required to initiate and reactivate the site may not make their involvement worthwhile. We will describe strategies we are using to overcome these challenges.

Regulation and governance of multinational drug trials in stroke: barriers and possibilities.

Over the last 10 years, there has been stagnation in the number of multinational drug trials in stroke in Europe. One important cause of this is probably the increased burden of laws and regulations that came with the European Union Clinical Trials Directive. The main objective of research regulation and governance should be to protect research participants, their tissues, and data, but the approval systems are complex, regulation is variably interpreted and enforced, and the assessment of studies is often not proportionate to the risk of the research to participants. Such unnecessary barriers should be reduced by simplifying, centralizing, and harmonizing the application process, and by applying regulatory and governance requirements in a way that is proportionate to the potential harms to the patients. The traditional functions of a regulator (in setting, monitoring, and enforcing quality standards) could also be supplemented with an aim to actively help researchers achieve these standards, for example, by giving advice, and ultimately with an aim to facilitate and promote research, for example, by integrating research in everyday clinical practice. Research networks offer one way of integrating research and clinical practice across multiple centers, and can streamline research delivery by supporting researchers deal professionally and efficiently with the regulations and governance requirements.

124IN - Phase I Cancer Drug Development in Europe

ABSTRACT Early drug development (EDD) in Europe is today very much in line with EDD in the USA in terms of regulatory process, timelines, and methodological approaches. However in Europe, approval for clinical trials of new agents is the responsibility of each member state, with each country providing its own regulatory authority. In that same direction the EU Clinical Trials Directive (CTD) provides the principles (derived from ICH-GCP), which are however interpreted and converted to law separately by each member state (1). While historically cooperative groups used to be strong stakeholders of EDD in the EU (ie, the Early Clinical Trials Group of the EORTC, SENDO, the Experimental Cancer Medicine Network of Cancer Research UK, CESAR), there is a clear trend towards the emergence of individual phase I centers where the expertise and the reputation for the conduct of these studies has been firmly established. Among those centers, the largest ones (by number of new patients enrolled in phase I/year) encompass: the Drug Development Unit at The Royal Marsden in London, the Vall D'Hebron Institute of Oncology in Barcelona, and the Drug Development Department (DITEP) at Gustave Roussy in Paris. Recently a retrospective analysis of phase I data from 14 European Institutions has demonstrated that phase I trials are characterized by a 50% likelihood of patient benefit (ie PR, SD) and a very low risk of toxic death (0.5%) (2). In collaboration with pharmaceutical companies and academia, an EORTC-led initiative, DLT-TARGETT, collected data encompassing 24 918 adverse events from 2084 patients included in 54 completed phase 1 trials. This initiative concluded that a) dose-increment recommendation need to take into account all available information, notably DLTs observed beyond cycle 1 in prior (and current, if feasible) dose levels b) any toxicity – whatever the grade - leading to a significant decrease in RDI should deserve particular attention c) the Recommended Dose for further studies should incorporate all available information - notably toxicities observed after C1 and intolerable clinical G2 toxicities - and be based on achieving > 75% RDI (3)

Emergency research and the interests of participants

The UK Clinical Trials Regulations were amended in 2006 and 2008 to facilitate research on medicinal products administered in emergency situations. The Regulations, which implement the EU Clinical Trials Directive, had previously required prior consent to participation in a clinical trial from either the participant or the participant’s legal representative. These amendments put emergency research on medicinal products on a similar footing to research on other types of invasive emergency treatment. This article argues that this was a positive development from the perspective of science and society and one for which there is a strong ethical basis. Nonetheless, it is argued that the UK Regulations cannot be interpreted consistently with European law without distortion contrary to the rule of law. It is also argued that the Directive needs to be amended or replaced to ensure a proper balance between the interests of participants and the interests of science and society. A number of specific suggestions are made, and the proposals made by the European Commission in July 2012 are supported. It is, however, argued that more needs to be done to protect the conduct of emergency trials from the conflicts of interests and biases that generally beset clinical trials.

An agenda for UK clinical pharmacology: The roles of clinical pharmacologists in UK universities

Clinical pharmacologists in universities play major roles in research and teaching and provide important contributions to National Health Service (NHS) activities, such as work for research ethics, drug and therapeutics, and clinical governance committees. Their research extends from preclinical studies using drugs to understand physiology and the mechanisms of disease to large‐scale clinical trials and population studies. This work is truly translational, with a focus on drugs and medicines and an emphasis on efficacy and safety. The lack of an organ base has allowed clinical pharmacologists to follow their interests wherever they lead, but their visibility has been hampered by successive earlier versions of the General Medical Council's Tomorrow's Doctors document, which undermined some of the necessary scientific underpinning of medical practice and reduced the time clinical pharmacologists had to interact with medical students and recently qualified doctors at the point of choosing their careers. Additional problems have arisen from the stifling effect of the European Union Clinical Trials Directive, and its UK interpretation, on clinical research. For future success, clinical pharmacologists need to embrace translational research, use recent changes to Tomorrow's Doctors, linked to the creation of safe prescribing skills, to spend more face‐to‐face time with their students, fight for a simplification and proportionate regulation of research, and persuade doctors, health service planners and the government of the importance of clinical pharmacology for UK clinical research, the NHS, patient safety and creation of health and wealth.

Re-engineering the European Union Clinical Trials Directive

Re-engineering the European Union Clinical Trials Directive

Awareness detection in anaesthesia during otorhino-maxillofacial surgery using bispectral index - monitoring technology

Awareness is characterized by intraoperative presence of consciousness and recollecting of the events occurring during general anaesthesia. The study was aimed at detecting awareness during general anaesthesia in otorhino-maxillofacial procedure. The study is a part of a prospective, phase IV academic study carried out at the Department for Otorhinolaringology, Clinical Centre of Serbia, and Maxillofacial Surgery. The study was approved by the Ethics Committee of the Clinical Centre of Serbia and performed in accordance with European Union Clinical Trials Directive. The evaluation included 40 patients (T-propofol and E-sevofluran group) subjected to different surgical procedures (American Society ofAnesthesiologists I-III). Depth of anaesthesia was monitored during surgical procedures according to the hemodynamic parameters (blood pressure, pulse, oxygen saturation, electrocardiography, capnometry). Bispectral index monitoring was applied; however, the insight into the obtained bispectral index values was possible only after the completion of the surgery when the comparison with hemodynamic values was performed. Modified Brice interview was postoperatively applied to the patients in whom awareness was suspected. Based on the hemodynamic parameter values obtained in 40 anesthetized patients, no cases of awareness were expected. After the completion of the surgical procedures, the recorded graphic and numeric bispectral index values obtained in the course of anaesthesia were analyzed. Higher bispectral index values (BIS > 60) were recorded in 1 T-group patient. It is possible to miss an awareness episode without using bispectral index technology monitoring during general anaesthesia in otorhinolaryngology and maxillofacial surgery. Bispectral index monitoring should be the clinical standard in general anaesthesia.

The EU Clinical Trials Directive Jeopardises Consumer and Occupational Safety

Contact DermatitisVolume 65, Issue 5 p. 251-253 The EU Clinical Trials Directive Jeopardises Consumer and Occupational Safety Axel Schnuch, Axel SchnuchSearch for more papers by this authorWolfgang Uter, Wolfgang UterSearch for more papers by this authorIan R. White, Ian R. WhiteSearch for more papers by this author Axel Schnuch, Axel SchnuchSearch for more papers by this authorWolfgang Uter, Wolfgang UterSearch for more papers by this authorIan R. White, Ian R. WhiteSearch for more papers by this author First published: 10 October 2011 https://doi.org/10.1111/j.1600-0536.2011.01998.xCitations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume65, Issue5November 2011Pages 251-253 RelatedInformation

Novel uses of coded data in clinical trials.

6143 Background: The EU Clinical Trials Directive has had an adverse impact on academic clinical research by increasing regulatory burdens that fall to staff whose primary roles are not trial related. In particular, documenting of clinical events is costly and often incomplete. One way to improve compliance whilst decreasing costs would be to use automated National Health Service (NHS) coded data. We set out to assess completeness of reporting of skeletal related events (SREs) post-progression within a clinical trial in bony metastatic prostate cancer (Trapeze, ISRCTN12808747). As these occur outside of the trials clinic environment, we examined the viability of using coded data in place of conventional case report form (CRF) collection. Methods: Hospital notes were reviewed to determine the occurrence of SREs in 86 men (median age 69; range 49-84) enrolled in Trapeze. These figures were used as our gold standard. SREs were classified into: (a) radiotherapy (RT) to treat bone metastases and (b) other (hypercalcaemia, cord compression, fracture and change of cancer therapy). SRE incidence was also determined by review of CRFs, and interrogation of the RT & NHS coding databases. These were both compared to the gold standard and with each other. Results: Sixty SREs were detected by notes review: 39/60 (65%) comprised RT to treat bone metastases, whilst 21/60 (35%) comprised others. Trial CRFs missed 36/39 (92%) RT SREs and 13/21 (62%) non-RT SREs. The departmental RT database detected 39/39 (100%) of RT SREs, whilst the NHS coding database missed 18/21 (86%) non-RT SREs. No SREs were detected by coding that did not appear in the notes review. Conclusions: In this study, post progression CRFs were highly inaccurate and trial procedures are being modified. For bone RT as an SRE, coded data matched the gold standard and could safely be substituted for standard CRF collection. For non-RT SREs both trial CRFs and NHS coded data were inaccurate in comparison with notes review. Data captured in academic trials needs to be carefully targeted to ensure maximum accuracy and minimal impact on personnel not directly associated with the study. For selected events, traditional CRFs can be reliably replaced with automated data capture from NHS databases, and this practice should be encouraged and expanded. No significant financial relationships to disclose.

SEEN BUT NOT HEARD? CHILDREN IN CLINICAL TRIALS

The Medicines for Human Use (Clinical Trials) Regulations put into effect the European Union Clinical Trials Directive 2001, which aims to facilitate and harmonise standards in research across Europe. The Regulations apply only to ‘clinical trials of investigational medicinal products’ (CTIMPs). The author discusses the consent requirements which restrict the ability of competent minors to consent or assent. Additionally, concerns are raised regarding the risk benefit ratio applied in paediatric clinical trials. The Regulations may prove overly restrictive of research which is not of direct benefit to the research participants, to the detriment of child health generally.

Conducting a European multi-center trial: first experiences with the new EU Clinical Trials Directive from an academic perspective

In 2001 the European Union adopted the EU Clinical Trials Directive (2001/20/EC) as a framework for good management in trials of medicines [4]. Many concerns were expressed that this Directive would impede and inhibit publicly funded clinical trials [2, 7, 14]. The question is if the concerns regarding the Clinical Trials Directive were legitimate. In other words, has the Directive really made it practically impossible for a group of surgeons to initiate, organize and conduct a European multi-center study? But also, has the new Directive achieved the goal of simplifying and harmonizing the administrative provisions governing clinical trials in EU countries? As a University Medical Center, we have experienced the practical consequences of the Clinical Trials Directive at first hand during a European multi-center study on instrumented lumbar spinal fusions with the use of Osteogenic Protein-1 (OP-1). The objective of this paper is to provide insight in the difficulties involved while conducting such a European multi-center study under the new EU Clinical Trials Directive.

Recommendations in relation to the EU Clinical Trials Directive and Medical Research Involving Incapacitated Adults

Recommendations in relation to the EU Clinical Trials Directive and Medical Research Involving Incapacitated Adults

A brave new Europe with the introduction of the EU Clinical Trials Directive: Impact upon the pharma industry and academic research with special emphasis on pharmacovigilance

1st May, 2004, saw the national implementation of the EU Clinical Trials Directive (2001/20 EEC). Additionally, Europe changed from 15 to 25 member states, all implementing the Directive nationally at the same time and all being affected by the many and varied aspects covered in the Directive. The paper looks at the new changes to European clinical trials and what this will mean for the pharmaceutical industry and research academia alike, especially in relation to safety reporting and risk/benefit assessments.

A brave new Europe with the introduction of the EU Clinical Trials Directive: Impact upon the pharma industry and academic research with special emphasis on pharmacovigilance

1st May, 2004, saw the national implementation of the EU Clinical Trials Directive (2001/20 EEC). Additionally, Europe changed from 15 to 25 member states, all implementing the Directive nationally at the same time and all being affected by the many and varied aspects covered in the Directive. The paper looks at the new changes to European clinical trials and what this will mean for the pharmaceutical industry and research academia alike, especially in relation to safety reporting and risk/benefit assessments.

The new EU Clinical Trials Directive and Orphan Medicinal Products: current status and recommendations

AbstractThe European Union (EU) ‘Clinical Trials’ directive will be implemented in all EU member states in May 2004 and will have a significant impact on clinical research in the EU. Its advent has caused a stir amongst commercial companies and academics alike and many even argue that it should not lead to excessive administration. Its implementation should therefore be carefully coordinated to avoid stifling valuable, potentially life‐saving research. It may particularly affect trials with orphan medicinal products, in rare genetic diseases or in oncology. These can be more difficult to manage due to complex or poorly understood disease pathology and the need to involve multiple trial sites with experts in different countries. This article illustrates the complexity of such trials, contains a brief analysis of the Directive, highlights the importance of a ‘flexible’ approach to trial design and conduct and includes a list of recommendations that could accompany the implementation of the Directive. Copyright © 2004 John Wiley & Sons, Ltd.

The Handbook of Clinical Trials and Other Research

There are many ways to do research and many pitfalls lurking for the unwary unthinking or uncritical. A huge amount of research material is produced annually but greater quantity does not necessarily mean greater quality. This book will provide the tools to design deliver and determine good quality research. This practical handbook includes all the main clinical trial and general research terms and is illustrated with real-life examples diagrams and tables. It also includes material on research ethical committees and incorporates recent international developments such as the EU Clinical Trials Directive. The research methods and issues identified are universal crossing countries and disciplines. It can be used as a reference tool an introduction to learning about clinical trials as a refresher to those involved in clinical research or to check that the correct terms are being used in the correct context. Readily available references are included that can be used by the reader to further support their own work. Healthcare professionals involved in clinical research evidence-based medicine and clinical trials will find it an essential user-friendly resource.