ERANET JTC 2011: Submission and Activation of an International Academic Translational Project in Advanced Breast Cancer. Experience From the ET-FES Study

Academic; Radiopharmaceuticals; Regulatory in EuropeAcadèmic; Radiofàrmacs; Regulador a EuropaAcadémico; Radiofármacos; Regulador en EuropaBackground: Academic research is important to face unmet medical needs. The Oncological community encounters many hurdles in setting up multicenter investigator-driven trials mainly due to administrative complexity. The purpose of a network organization at a multinational level is to facilitate clinical trials through standardization, coordination, and education for drug development and regulatory approval. Methods: The application of an European grant foresees the creation of a consortium which aims at facilitating multi-center academic clinical trials. Results: The ERA-NET TRANSCAN Call 2011 on “Validation of biomarkers for personalized cancer medicine” was released on December 2011. This project included Italian, Spanish, French and German centers. The approval process included Consortium constitution, project submission, Clinical Trial Submission, and activation on a national level. The different timescales for submitting study documents in each Country and the misalignment of objections by each Competent Authority CA, generated several requests for changes to the study documents which meant amendments had to be made; as requested by the 2001/20/EC Directive, the alignment of core documents is mandatory. This procedure impacted significantly on study activation timelines. Time to first patient in was 14, 10, 28, and 31 months from the date of submission in Italy, France, Spain, and Germany, respectively. Accrual was stopped on 22nd January 2021 due to an 18F FES shortage as the primary reason but also for having exceeded the project deadlines with consequent exhaustion of the funds allocated for the project. Conclusions: Pharmaceutical companies might be reluctant to fund research projects aimed at treatment individualization if the approval for a wider indication has already been achieved. Academic trials therefore become fundamental for promoting trials which are not attractive to big pharma. It was very difficult and time consuming to activate an academic clinical trial, for this reason, a study may become “old” as new drugs entered into the market. National institutions should promote the development of clinical research infrastructures and network with competence in regulatory, ethical, and legal skills to speed up academic research.This research received grants from ERANET JTC 2011

Evaluating the effectiveness and risks of oral anticoagulant treatments in multimorbid frail older subjects with atrial fibrillation using the multidimensional prognostic index: the EURopean study of older subjects with atrial fibrillation-EUROSAF

Background Previous studies suggested that a different risk of mortality may influence the oral anticoagulant prescription in older patients with atrial fibrillation (AF). Recently, the Multidimensional Prognostic Index (MPI) demonstrated a high grade of accuracy, calibration and feasibility to predict mortality in hospitalized and community-dwelling older people. Prognostic information, as calculated by the MPI, however, is not included in the decision algorithm of treatments in older patients with AF Purpose The aim of this international multicenter prospective observational study was to evaluate whether a different prognostic profile, as determined by the MPI, is associated with different treatments for AF (no treatment vs oral anticoagulants) and differences in the main outcomes, i.e., mortality, major thromboembolic events and side effects. Materials and methods Older hospitalized patients (age >= 65 years) with non-valvular AF will be consecutively enrolled in an European, cross-national, prospective, observational study. At baseline, functional and clinical information will be collected to calculate the MPI, CHA2DS2-VASc score, HAS-BLED score, pharmacological treatments (and the compliance during follow-up) and main and secondary diagnoses. During the 12-month follow-up period, information on survival, major thromboembolic events and major bleeding will be collected. For these aims, a sample size of 3000 people was deemed as sufficient. Conclusions The EUROSAF study has the main objective of evaluating in a population of hospitalized older subjects with AF the clinical benefit/risk ratio of the oral anticoagulant treatments in terms of mortality, major thromboembolic events and bleeding side-effects, giving important information regarding the appropriate prescription of anticoagulant therapy in this population

The PRO‐HOME Project. A multicomponent intervention for the protected discharge from the hospital of multimorbid and polytreated older individuals by using innovative technologies: A pilot study

BackgroudDischarge planning from the hospital of frail older patients is an important step to avoid inappropriate long-stay hospitalizations and to prevent the risks related to the prolonged hospitalization. In this frame, we developed an experimental trial-'PRO-HOME', a multicomponent programme of interventions for multimorbid and polytreated hospitalized older patients.AimThe main aim of the study was to develop a protected discharge facility using a mini apartment equipped with advanced architectural and technological components to reduce the length of hospital stay of older participants (aged 65+ years old) admitted to the hospital for an acute event, deemed stable and dischargeable.Materials and MethodsThis is a pilot randomized controlled study, comparing 30 hospitalized participants included in a multidimensional, transitional care programme based on information and communication technologies to 30 patients in standard usual care until hospital discharge.ResultsWe presented the study design of the PRO-HOME programme, including architectural and technological components, the enrolment procedures, the components of the intervention that is physical activity, cognitive training and life-style education and the evaluation method of the intervention based on the Comprehensive Geriatric Assessment to explore the changes in the individual domains that are target of the multicomponent intervention.ConclusionsThe final results will suggest whether the PRO-HOME programme represents a useful and feasible intervention to reduce the length of hospital stay of multimorbid and polytreated hospitalized older patients and improve their physical and cognitive performances and overall quality of life.Patient or Public ContributionDue to the characteristics of the population of interest of the PRO-HOME study, we involved in the study design and programme of the activities the participants enrolled in a previous smart home-based project named MoDiPro carried-out during a 3-year period. The elderly participants from the local population involved were asked, by means of focus groups, for feedback on their experience in MoDiPro, and their suggestions were integrated into the design phase of the current PRO-HOME project. The focus groups included open group interviews with a qualitative collection of the patients' feedback so that the participants could interact with each other

A phase I-II preoperative biomarker trial of fenretinide in ascitic ovarian cancer

Purpose: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment. Methods: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography. Results: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 μmol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 μmol/L 4-HPR. Conclusions: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention. Copyright © 2006 American Association for Cancer Research

ERANET JTC 2011: Submission and Activation of an International Academic Translational Project in Advanced Breast Cancer. Experience From the ET-FES Study

International audienceBackground: Academic research is important to face unmet medical needs. The Oncological community encounters many hurdles in setting up multicenter investigator-driven trials mainly due to administrative complexity. The purpose of a network organization at a multinational level is to facilitate clinical trials through standardization, coordination, and education for drug development and regulatory approval. Methods: The application of an European grant foresees the creation of a consortium which aims at facilitating multi-center academic clinical trials. Results: The ERA-NET TRANSCAN Call 2011 on “Validation of biomarkers for personalized cancer medicine” was released on December 2011. This project included Italian, Spanish, French and German centers. The approval process included Consortium constitution, project submission, Clinical Trial Submission, and activation on a national level. The different timescales for submitting study documents in each Country and the misalignment of objections by each Competent Authority CA, generated several requests for changes to the study documents which meant amendments had to be made; as requested by the 2001/20/EC Directive, the alignment of core documents is mandatory. This procedure impacted significantly on study activation timelines. Time to first patient in was 14, 10, 28, and 31 months from the date of submission in Italy, France, Spain, and Germany, respectively. Accrual was stopped on 22nd January 2021 due to an 18F FES shortage as the primary reason but also for having exceeded the project deadlines with consequent exhaustion of the funds allocated for the project. Conclusions: Pharmaceutical companies might be reluctant to fund research projects aimed at treatment individualization if the approval for a wider indication has already been achieved. Academic trials therefore become fundamental for promoting trials which are not attractive to big pharma. It was very difficult and time consuming to activate an academic clinical trial, for this reason, a study may become “old” as new drugs entered into the market. National institutions should promote the development of clinical research infrastructures and network with competence in regulatory, ethical, and legal skills to speed up academic research