In particular, CRAs and PIs highlighted the strengths and weaknesses encountered in the study conduction with particular reference to the following issues:

• Informed consent procedure

• Planning study visits

• IMPs handling

• Dose adjustments for Safety and Efficacy reasons

• Periodic assessments for Safety

• Data entry in e-CRF

• Collection of Ferritin Samples for centralized evaluations and MRI Scans

• Study documentation

• Pharmacovigilance

• Monitoring activities.

The gathered information have provided updated information on all the centres involved in the study and are essential to identify the main issues to be solved to increase the effectiveness of the study and to ensure patients’ safety and high quality of collected data.

The last patients were included in Albania, Italy and UK while the 393rd patient has been randomized on 14/7/2016 in UK.

An important action carried out by the DEEP-2 Trial Management Team aimed at ensuring the correct implementation of the study protocol is the release of a monthly DEEP-2 study newsletter (available on the DEEP website in the Study Newsletter section), that is sent to all PIs and also available on the website, aimed at clarifying most of the criticisms of the study protocol.

Stay connected with the DEEP website and social networks (Facebook and Google+) to be updated.

The DEEP-2 study actually involves a total of 227 patients included in 32 recruiting centres: Italy (51), Egypt (123), Greece (9), Albania (25) Tunisia (7) and UK (10). The first nine patients have been enrolled in UK and 10 in Tunisia this week. The enrollment will terminate when 344 patients will have been randomized.

Further 5 new centres in Turkey (Hacettepe University, Faculty of Medicine in Ankara; Istanbul University, Cerrahpaşa Faculty of Medicine in Istanbul; Kanuni Sultan Suleyman TRH in Istanbul; Mersin University Faculty of Medicine in Mersin; Akdeniz University Medical Faculty in Antalya), 1 in Lebanon (Nini Hospital in Tripoli), 1 in Albania (Hospital ‘Ihsan Çabej’ in Lushnjë) and 1 in Qatar (National Center for Cancer Care and Research in Doha) have been contracted and are very close to recruit their first patients. The centers in Cyprus and Morocco are waiting for the last authorization before they can be activated.

In order to ensure the correct implementation of study protocol and speed up the recruitment phase, the DEEP Management Team has issued a new version (2.0) of the Study Procedure Manual both in PDF format and hard copy to be sent to each site. This version is specifically addressed to the clinical investigators aiming at facilitating consistency with protocol implementation among study sites and to be an on hand reference to solve doubts/questions that may arise during the study conduction.

Moreover, all PIs regularly receive a monthly DEEP-2 study newsletter with an update of the patients’ enrolment and the FAQ section, available on the website, aimed at clarifying most of the criticisms of the study protocol.

Stay connected with the DEEP website and social networks (Facebook and Google+) and look at the counter on the homepage to be updated on the DEEP-2 patients recruitment status!

The report provided a comprehensive overview of the activities performed with particular reference to the implementation of the DEEP studies in compliance with the Paediatric Investigation Plan (EMEA-001126-PIP01-10), as approved and further amended by the Paediatric Committee (PDCO).

The main efforts of this reporting period have been devoted to implement DEEP 2 recruitment and study conduct. In particular, in order to reach the required patient number, the number of clinical centers has been increased, recruitment capacity has been checked and study qualification visits have been performed.

As stated in the report, even if the main project activities have been completed and the great majority of the deliverables and milestones foreseen for that period have been addressed, many delays have occurred mainly due to the lengthy approval process imposed by many local ethics committees and competent authorities. These problems have led to a request of amendment of the DEEP Grant Agreement, which has been approved on 10.06.2015 by the European Commission providing an extension of 20 months of the project. The specific reasons for requesting this extension have been:

• prolonged difficulties due to the political instability in two of the North African countries, Egypt and Tunisia, which were representing over 50% of the total potential patients recruitment;

• need to identify new recruiting centres;

• changes in Regulatory Procedures for authorisation of the studies in different countries;

• changes in the DEEP 2 study protocol as included in a modified agreed PIP.

Furthermore, DEEP has also faced many regulatory issues that led on 26/08/2014 (following a Letter of intent on June 2014) to a request for modification (RfM) of the agreed PIP to the European Medicines Agency (EMA) and its Paediatric Committee (PDCO). The procedure ended on 17/11/2014 as described in the figure below.

The PIP modification was motivated by the need to implement the results of the modification introduced by the scientific coordination group into the DEEP 2 protocol as well as it was intended to clarify minimal aspects on timing and use of data with reference to DEEP-1 and DEEP-3 studies. In this context and to create the conditions for operating according to the European ethical and regulatory legislation, the DEEP Coordinator has developed specific standard operating procedures (SOPs) and guidelines to be implemented by all DEEP Beneficiaries.

As a result, the DEEP project’s commitment of operating according to the European ethical and regulatory legislation has ensured and will still guarantee the implementation of ethics principles and GCP recommendations in all participating centres, including those located outside the European area, thus promoting the spread of such practices in clinical research.

On October 2015, 283 patients (86% of 328 subjects of the study population) were enrolled, 36 of which are currently in the prospective phase of the study. The observation, which aims to investigate serious and non-serious adverse reactions, as well as risk factors for ADRs related to deferiprone treatment, has ended for 166 patients. The mean observation time per patient was currently 2.1 years, with 595 person-years (84% of 711 person-years).

To date, the study is in the last collection episode for most of the centres involved (Tirana, Nicosia, Bari, Naples, Padua, Palermo and Florence) that will be closed for recruitment soon. The prospective arm of the study will be concluded in October 2015, while retrospective data will be collected until termination of the study with reference to the same period (up to October 2015).

Recently the study successfully received the ethical approval for two new centres in Casablanca (Hôpital 20 août and Hôpital Universitaire d’enfants Abderrahim Harrouchi) and the recruitment started at Centre National de Greffe de Moelle Osseuse (CNGMO) of Tunis.

Furthermore, the DEEP-3 Study Team is currently in the process of including two new centres in Egypt: Alexandria and Zagazig.

This event represents an important step both for the study, with the recruitment of the first paediatric patients in Albania in a not-for-profit study, but also for the patients themselves, having the chance to be undergone to a diagnostic procedure, which is, today, deemed necessary from major European guidelines and not currently available in-house.

This represents an important achievement since it highlights that almost all centres, the majority of Italian ones, Atene, Cairo and Tirana, are now ready to enroll patients.

In our estimation, within April 2015 all the centres involved in the DEEP-2 clinical trial will have started the enrollment phase.

The 5^th DEEP General Assembly took place from the 3^rd to the 5^th of July 2014 in the legendary city of Athens, Greece, with the participation of the whole DEEP Consortium as well as external experts. The main contents presented and discussed are summarized below.

Session I: DEEP-1 Results
The meeting opened with the presentation of the results of the pharmacokinetic study (DEEP-1 trial) and their impact on the DEEP-2 study conduct. The collected data provide valuable information on the correct dosage of deferiprone to be administered to children below 6 years of age. Although multicentre trials are particularly difficult for PK evaluations, the team congratulates the investigators and all the study staff as data collected within DEEP-1 are excellent.

Session II: Organization of the DEEP-2 Trial
The DEEP-2 trial implementation, in terms of authorisation process and status, IMPs distribution, technical facilities was discussed. Moreover, the psychological sub-study to investigate parents’ behaviour during the DEEP-2 recruitment phase was presented. The main questions and queries arisen during the first weeks of recruitment were discussed and common actions/solutions were shared and agreed upon and included in the DEEP-2 FAQ.

Session III: DEEP-2 Recruiting Centres
The importance to adopt proper communication strategies and flows between the Sponsor’s staff and Investigators’ team, even when face-to-face interactions are not possible, was stressed in order to guarantee the best management of each trial procedure. In particular, the monitoring procedures to be carried out were described and the experience of the already performed monitoring visits with the most challenging issues was shared.

Session IV: DEEP-3 Long Term Safety Study
After the presentation of the preliminary results and the criteria for Adverse Drug Reaction and Adverse Events assessment, the discussion focussed on the slow recruitment process observed so far. Strategies to accelerate recruitment were discussed. Sample size calculation based on the number of patients and patients’ age is proposed and will be conducted in the following weeks. Moreover it was clarified that any use of deferiprone both as monotherapy and in combination will deferoxamine is currently included in the protocol.

Scientific Open Session
The GA presented the opportunity to hold an open Scientific Meeting on July 5^th, which focussed on specific topics of interest in the field of iron chelators and iron overload where eminent scientists and experts provided an overview of:

– the new paediatric clinical trial regulation;

– the main features of deferiprone therapy, either alone or in combined regimen, in terms of safety, efficacy and significant clinical evidence in hepatic and cardiac iron overload;

– the management of iron overload in Sickle Cell Disease;

– the importance of Magnetic Resonance Imaging analysis;

– the new therapies for the treatment of Hepatitis C virus Infection.