scholarly journals Ethical Issues and Barriers for Multi-National Paediatric Clinical Trials: The Challenging Experience of the DEEP Project

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4820-4820
Author(s):  
Viviana Giannuzzi ◽  
Mariagrazia Felisi ◽  
Hugo Devlieger ◽  
Aurelio Maggio ◽  
George Papanikolaou ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ethical Issues ◽  
Descriptive Analysis ◽  
National Level ◽  
Comparative Trial ◽  
Phase Iii ◽  
Eu Countries ◽  
Paediatric Trial ◽  
Significant Difference ◽  
The Eu

Introduction: The procedures and requirements for the clinical trial application (CTA) to Ethics Committees (ECs) and/or Competent Authorities (CAs) are not fully harmonised, and this is even more evident when non-EU countries are involved. This lack of harmonisation makes more difficult the approach in the case of 'small populations', such as children and patients affected by rare diseases. A phase III efficacy-safety comparative trial (DEEP-2) involving paediatric patients affected by transfusion dependent haemoglobinopathies from seven European and non-European countries (Albania, Cyprus, Greece, Italy, United Kingdom, Egypt, Tunisia) was carried out in the context of a FP7 project (HEALTH-F4-2010-G.A. n. 261483) and included in an agreed Paediatric Investigation Plan. Aims: The aims of this paper are to describe in a complex multi-national/multi-ethnic framework the different provisions and procedures to authorise a paediatric trial in EU/non-EU countries and to evaluate the possible impact of the following key indicators on the timing of ECs approval and CAs authorisation: complexity of the national/local provisions and procedures to authorise a paediatric trial, including the number of ECs and CAs to be addressed; number and type of additional local/national documentation; number of queries from CAs and ECs; geographic setting (EU and non-EU). Methods: The following information was collected from official websites and through a survey addressed to Principal Investigators: The regulatory and legal frameworks in force at the time of the submission of DEEP-2 in each involved country;The procedures required at local/national level (i.e. number of ECs and CAs to be addressed, parallel or subsequent submission to the CA and the EC, preparation of the CTA form and documents required from CAs and ECs);The timing of ECs approval and CAs authorisation, including number and types of queries, were collected from DEEP-2 Trial Master File. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model (GLM) analysis were used to describe results and to analyse significance of the considered indicators. Results: In the EU countries, relevant legislative acts apply and include GCP and specific procedures for paediatric trials, in non-EU countries GCP guidelines apply but have not been implemented in the national laws regulating clinical trials. Moreover, within the 4 EU Member States a different approach was in place, even if under the same rules (i.e. Directive 2001/20/EC as implemented in the national law) with distinctive documents required for the CTA in almost all the EU countries compared with the EC provisions. The CTAs were performed in the period June 2012 - September 2015 in 23 trial sites. The EC approvals and CA authorisations were issued between January 2013 - September 2015. In the EU countries, the authorisation process was completed within 7,3 to 33,8 months (median = 15 months), while in non-EU countries, the authorisation process was completed by 7 months (median = 4 months) (figure 1). In particular, the comparison of the CA time authorisation shows a significant difference between EU and non-EU clusters (p = 0.001); however, if the statistical model is adjusted for the number of EC requests as covariate, the difference is not significant. Thus, it seems that the main factor influencing the time for EC approval is the number of requests for changes/clarifications (mainly on informed consent/assent, study protocol, insurance) (figure 2). Conclusion: Delays in completion of the authorisation phase in many countries seems to be a relevant issue and the timeframes for the authorisation in EU countries are not compliant with the European requirements (60 days for single opinion release and 30 days for its acceptance, as stated in Directive 2001/20/EC). The main reasons for delay is the complexity of the procedures and the requests from the ECs/CAs. In non-EU countries, procedures are different and faster with less requests from ECs and CAs. The upcoming application of a stronger set of rules, CT-Regulation (EU) 536/2014, is expected to harmonise practices in Europe and possibly outside Europe. The final aim of this change should be to assure a good balance between a timely approval and a high-level of children protection. Disclosures Reggiardo: CVBF: Consultancy. Tricta:ApoPharma: Employment.

scholarly journals Number of clinical trials of new therapeutic agents in the European Union countries of Central and Eastern Europe, 2000–2019

2021 ◽  
Author(s):  
Mikołaj Bartoszkiewicz ◽  
Joanna Kufel-Grabowska ◽  
Maria Litwiniuk
Keyword(s):  
European Union ◽  
Clinical Trials ◽  
Clinical Research ◽  
Eastern Europe ◽  
Central And Eastern Europe ◽  
Phase Iii ◽  
The European Union ◽  
Eu Countries ◽  
Phase Iii Trials ◽  
The Eu

Introduction: The clinical research market of the European Union (EU) countries of Central and Eastern Europe has been experiencing a dynamic growth of clinical trials in the last 10 years. Oncology and cardiology are the areas where the most clinical trials are conducted. Aim: This study aims to analyze the clinical research market including countries, medical fields and trial phases in the EU countries of Central and Eastern Europe. The comparative analysis of countries is divided into 5-year periods. Material and methods: Clinical research market analysis was carried out in 11 EU countries of Central and Eastern Europe: Bulgaria, Croatia, Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia, and Slovenia. In searching for the number of clinical trials, the ClinicalTrials.gov database was used. Results and discussion: From 2000 to 2019, 6497 clinical trials were conducted in the EU countries of Central and Eastern Europe. There were 1840 clinical trials registered in Poland, 1188 in Czechia, and 1005 in Hungary. The most clinical trials were registered in the field of oncology (22%), followed by cardiology (16%) and neurology (12%). Phase III trials representing as much as 60% (n = 2854) of all conducted medical experiments. The highest increase in the number of clinical trials in the last two 5-year periods (2010–2014 and 2015–2019) was recorded in Estonia, at 471%. Conclusions: There has been a significant increase in the number of clinical phase III trials in the EU countries of Central and Eastern Europe, mainly in Poland, Czechia, and Hungary.

scholarly journals A Healthy Sense of Trust

2017 ◽  
Vol 2 (Suppl. 1) ◽  
pp. 1-10
Author(s):  
Denis Horgan
Keyword(s):  
European Union ◽  
Clinical Trials ◽  
Big Data ◽  
Data Protection ◽  
Fast Moving ◽  
Ethical Issues ◽  
Personalised Medicine ◽  
Drug Pricing ◽  
The Right ◽  
The Eu

In the fast-moving arena of modern healthcare with its cutting-edge science it is already, and will become more, vital that stakeholders collaborate openly and effectively. Transparency, especially on drug pricing, is of paramount importance. There is also a need to ensure that regulations and legislation covering, for example the new, smaller clinical trials required to make personalised medicine work effectively, and the huge practical and ethical issues surrounding Big Data and data protection, are common, understood and enforced across the EU. With more integration, collaboration, dialogue and increased trust among each and every one in the field, stakeholders can help mould the right frameworks, in the right place, at the right time. Once achieved, this will allow us all to work more quickly and more effectively towards creating a healthier - and thus wealthier - European Union.

Economic Growth In The Conditions Of Digitalization In The EU Countries

2021 ◽  
Vol 38 (4) ◽  
Author(s):  
Oleksandr Vyshnevskyi ◽  
Ihor Stashkevych ◽  
Olena Shubna ◽  
Svetlana Barkova
Keyword(s):  
Economic Growth ◽  
Economic Development ◽  
European Commission ◽  
National Level ◽  
Present Stage ◽  
Eu Countries ◽  
Stage Of Development ◽  
Object Of Study ◽  
High Level ◽  
The Eu

The article discusses the dynamics of economic development based on the level of digitalization of the countries. Economic development is evaluated through the dynamics of GDP changes. Digitalization level is evaluated through the Digital Economy and Society Index (DESI), which is calculated on a regular basis by the European Commission. Object of study – 28 EU‑member countries. The hypothesis of the investigation: a high level of digitalization leads to an acceleration of economic growth on national level. This hypothesis did not find any statistically significant confirmation. Thus, we can conclude that the level of the economy digitalization at the present stage of development of technologies and institutions in the EU countries does not have a decisive effect on the rate of economic growth.

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

1987 ◽  
Vol 5 (6) ◽  
pp. 851-861 ◽  
Author(s):  
L H Baker ◽  
J Frank ◽  
G Fine ◽  
S P Balcerzak ◽  
R L Stephens ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Actinomycin D ◽  
Malignant Tumors ◽  
Soft Tissue Sarcomas ◽  
Comparative Trial ◽  
Phase Iii ◽  
Oncology Group ◽  
Southwest Oncology Group ◽  
Significant Difference

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Trends in case-control allocation in phase III randomized cancer clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14582-e14582
Author(s):  
Shruti Gupta ◽  
Swathi Gopishetty ◽  
Srishti Malhotra ◽  
Vamsi Kota ◽  
Anand P. Jillella ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Trial Design ◽  
Phase Iii ◽  
Cancer Clinical Trials ◽  
Unequal Distribution ◽  
Equal Distribution ◽  
Advantages And Disadvantages ◽  
Significant Difference ◽  
And Control ◽  
Unequal Allocation

e14582 Background: Patients enrollment in cancer clinical trials has traditionally been limited to an equal distribution between cases and controls. Some clinical trials have an unequal distribution between the case and control arm. Although such unequal allocation is uncommon it has certain advantages and disadvantages to it. The trend and proportion of cancer clinical trials that have an unequal allocation has not been studied. Methods: Data about cancer clinical trials was extracted from clinical trials.gov. The query included phase 3 trials which included adults and were conducted between 2010 to 2017. Only clinical trials that were either completed or active – but not recruiting were included. T test was used to determine statistical difference between different subgroups. Results: 601 clinical trials were identified of which 356 trials with two arms and 47 trials with 3+ arms were identified. Amongst the eligible 298 trials with two arms, there were 216 trials with equal allocation (1:1) and 82 trials with unequal allocation. Amongst the eligible 29 trials with 3+ arms; there were 21 trials with equal allocation (1:1:1) and 8 trials with unequal allocation. There was no significant difference in the proportion of trials with unequal allocation over the time period from 2010 to 2017. The categories of cancer which had the highest number of two arm clinical trials with unequal allotment were: genitourinary, breast and hematological malignancies (Table). Conclusions: Cancer clinical trials with unequal allocation between case and control arms have been common in the past decade. This may represent a new trend in clinical trial design to help enhance closer monitoring of adverse events despite higher costs attached to this method.[Table: see text]

scholarly journals SER 2020 - A comparative approach proving the EU tanning industry's continuous striving towards sustainable development

2020 ◽  
Author(s):  
Gustavo Gonzalez-Quijano ◽  
Dorel Acsinte ◽  
Gheorghe Bostaca
Keyword(s):  
Value Chain ◽  
Ethical Issues ◽  
Social Indicators ◽  
National Level ◽  
Age Distribution ◽  
Comparative Approach ◽  
Staff Retention ◽  
Leather Industry ◽  
Tanning Industry ◽  
The Eu

The paper presents results of the new Social and Environmental Report of the European Leather Industry (SER 2020) that follows up on the exercise done in 2012. Based on an intensive survey amongst European tanneries, led by COTANCE and industriAll-European Trade Union, company data on social indicators and environmental parameters that reflect the performance of the tanning sector were collected. Companies’ data, anonymised and aggregated at national level and centrally computed at European level are presented and analysed, versus 2012 data, where appropriate (in terms of average values). Social Footprint of the EU Tanning Industry (employment contracts, age distribution in the EU force, staff retention, education, citizenship, gender balance) and Environmental Footprint of the EU Tanning Industry (chemical consumption, energy consumption, breakdown of energy sources, water consumption, removal of water pollution, waste generation, solvent consumption, costs and investments) are thoroughly discussed. Finally, Sustainability priorities / Ethical issues for the value chain and Objectives and challenges for the future are communicated in order to demonstrate the continuous striving of Europe’s leather sector towards excellence in social and environmental performance.

Final results of study 20050181: A randomized phase III study of FOLFIRI with our without panitumumab (pmab) for the second‑line treatment (tx) of metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3535-3535 ◽  
Author(s):  
Alberto F. Sobrero ◽  
Marc Peeters ◽  
Timothy Jay Price ◽  
Yevhen Hotko ◽  
Andres Cervantes-Ruiperez ◽  
...  
Keyword(s):  
Descriptive Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Second Line ◽  
Primary Analysis ◽  
Primary Endpoints ◽  
Significant Difference ◽  
Secondary Endpoints ◽  
Event Rates

3535 Background: The primary analysis of study 20050181 showed that in patients (pts) with wild-type (WT) KRAS mCRC, pmab plus FOLFIRI given as second-line therapy significantly improved progression-free survival (PFS) vs FOLFIRI alone. Here, we report on a prespecified descriptive analysis planned for 30 months (mos) after the last pt was enrolled. Methods: Pts with mCRC, ECOG 0-2, who had one prior fluoropyrimidine-based chemotherapy regimen were randomized 1:1 to pmab 6.0 mg/kg Q2W+FOLFIRI (Arm 1) vs FOLFIRI (Arm 2). Co-primary endpoints were OS and PFS (central assessment). Secondary endpoints included objective response rate (ORR) and safety. Tumor KRAS status was determined by a blinded central lab. Results: 1186 pts were randomised and received tx: 591 in Arm 1, 595 In Arm 2. 1083 pts (91%) had KRAS results. Adverse event rates were consistent with the primary analysis. Results are shown below. Conclusions: In pts with WT KRAS mCRC receiving pmab+FOLFIRI vs FOLFIRI, PFS and ORR were significantly improved, and there was a trend toward improved OS. Post-progression anti-EGFR tx may have attenuated any significant difference in OS between tx arms. In pts with MT KRAS mCRC, no difference in efficacy was observed between tx arms. KRAS testing is critical to select appropriate pts for tx with pmab. [Table: see text]

Long-term responders and survivors on pazopanib for soft tissue sarcomas (STS): Subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10553-10553
Author(s):  
Bernd Kasper ◽  
Saskia Litière ◽  
Sandrine Marreaud ◽  
Stefan Sleijfer ◽  
Jaap Verweij ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Performance Status ◽  
Descriptive Analysis ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Phase Iii ◽  
Dose Modifications ◽  
Long Term Survivors

10553 Background: Pazopanib has recently received approval in US, EU & Japan for use in certain STS subtypes. We conducted a retrospective analysis on pooled data from two EORTC clinical trials on pazopanib in STS in order to characterize long term responders and survivors. Methods: Patients selected for analysis were treated with pazopanib in phase II study 62043 (n = 142) and phase III study 62072 (PALETTE) (n = 246). Combined median progression-free survival (PFS) was 4.0 months; median overall survival (OS) was 11.3 months. 34 % of patients had a PFS ≥ 6 months (n = 133) and were defined as long term responders; 33 % of patients survived ≥ 18 months (n = 128), defined as long term survivors. Following patient characteristics were studied: gender, age, performance status, tumor localization, histology, grading, treatment exposure and dose modifications, severity of adverse events and post protocol therapy. Results: Clinical cut-off dates for this analysis resulted in a pooled database with a median follow-up of 2.3 years. Patient characteristics were compared between four subgroups based on short / long term PFS and OS, respectively. 79 patients were both long term responders and long term survivors. The descriptive analysis confirmed the importance of known prognostic factors such as age, performance status and grading, but did not add additional characteristics translating into long term response or survival. We identified 12 patients remaining on pazopanib for more than two years: 9 aged younger than 55 years, 9 females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. Only two of those patients achieved a partial response; the remaining 10 experienced stable disease as best overall response. Median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. Four patients were still on pazopanib at the end of the studies with a median PFS of 2.3 years and a median OS of 2.8 years. Conclusions: 34 % and 33 % of STS patients given pazopanib in these studies have a long PFS and / or OS respectively. 3.1 % of patients demonstrate a clinical benefit even beyond 2 years.

Survival comparison analysis of two historical cohorts of metastatic renal cell carcinoma patients (cytokine therapy versus targeted agents): A European single-center experience over 26 years.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 513-513
Author(s):  
Georg C. Hutterer ◽  
Silvia V. Golbeck ◽  
Edvin Mrsic ◽  
Daniel Krieger ◽  
Angelika Bezan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Phase Iii ◽  
Targeted Agents ◽  
Entire Study ◽  
Significant Difference

513 Background: By the approval of new targeted agents in 2006, the standard of therapy in metastatic renal cell carcinoma (mRCC) changed, since they demonstrated significantly improved progression-free survival (PFS) rates compared with interferon in phase III clinical trials. Differences in overall survival (OS) could not be proven since many patients switched to another effective substance after progression of the disease. Thus, we compared two mRCC patient cohorts in order to detect OS differences between immunotherapy and targeted therapies in a real-life population outside controlled clinical trials. Methods: Clinico-pathological data from 594 mRCC patients, operated between 1984 and 2010 at a single tertiary academic center, were evaluated retrospectively with the null hypothesis, that there is no statistically significant difference in OS of patients treated either with interferon or targeted agents. Using electronical patient records, all data regarding the beginning, duration, lines, and different forms of therapies were assessed. Patients’ cancer-specific survival (CSS), as well as OS, were assessed using the Kaplan-Meier method, compared with the log-rank test. A first analysis revealed results for the entire study cohort. Subsequently, outcome analyses were restricted to mRCC patients with clear cell histology only. Results: With respect to the complete follow-up period, our results in both analyses did not show a statistically significant OS difference between the two therapy modalities. By limiting the observation period to 5 years after treatment initiation, a statistically significantly improved median five-year OS rate (26 mo.) for clear cell mRCC patients treated with targeted agents was observed, compared with 21 mo. in the interferon group (p=0.028). Conclusions: Our results confirm the presumption of an improved OS in mRCC attributable to treatments with targeted agents compared with previous cytokine therapies.

The EU regulatory network and emerging trends – a review of quality, safety and clinical development programmes

2021 ◽  
Vol 10 (2) ◽  
pp. 83-99
Author(s):  
Marta Zuccarelli ◽  
Benjamin Micallef ◽  
Mark Cilia ◽  
Anthony Serracino-Inglott ◽  
John-Joseph Borg
Keyword(s):  
Clinical Trials ◽  
Adverse Event ◽  
Phase I ◽  
Clinical Development ◽  
Phase Iii ◽  
Regulatory Requirements ◽  
Safety Concerns ◽  
Emerging Trends ◽  
Over Time ◽  
The Eu

Introduction/Study Objectives: The development of biosimilars is challenging due to the complexity of the active substances as well as the strict regulatory requirements to show similarity with a reference medicinal product. This review aims to describe the regulatory experience of approving biosimilars in the European Union (EU) within the EU framework, identify emerging trends in the EU regulatory pathway when approving biosimilars and discuss where the EU biosimilar framework is heading. Methods: Marketing authorisation applications (MAAs) submitted up to 2019 were retrieved from the public domain. The European public assessment report database was searched for approved biosimilars and clinical development programmes of biosimilars belonging to the same class were reviewed. In order to observe if biosimilars released onto the market increased safety concerns, we compared disproportionate adverse event reports pre- and post-licensure. Results: Up to December 2019, 90 MAAs were submitted and 53 biosimilars were approved for 14 different biologicals. Total number of clinical trials (both phase I and III) steadily goes up driven by an increase number of approvals in later years, while the average number of both phase I and III trials decreased over time with some with Pegfilgrastim biosimilars being approved without conducting any phase III clinical trials. No new safety concerns were identified from the analysis of disproportionate adverse event reports. Discussion: Clinical development programmes of biosimilars and the requirements set for biosimilars approval are changing over time. Biosimilars approved seem to be as well tolerated as the reference products when approved based on stringent regulatory requirements. Conclusion: Regulation of biosimilars is progressing as more knowledge is gained.

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