“The scope and objectives of the studies were recognized by all of us to be challenging, but the complexities, particularly of DEEP-2, the randomized controlled trial comparing deferiprone and deferasirox in the treatment of iron overload in children with hemoglobinopathies, exceeded expectations.  That the obstacles have now been overcome, albeit with much work over a longer period than we might have wished for, is due to the DEEP Management Team’s relentless local effort and experience, the trials’ dedicated clinical investigators, and ApoPharma’s knowledge and expertise in conducting clinical studies in many different countries. With DEEP-2 – he pointed out – the company has aimed to be a full partner in study design, logistics, and regulatory and pharmacovigilance interactions from the outset. Two ongoing relationships have been particularly noteworthy: one the collegial scientific and medical discourse among ApoPharma, DEEP HQ staff, investigators and contractors, and the other the friendships built mostly by email between ApoPharma and DEEP team members in managing the challenges of product supply to multiple sites on two continents. As we come to the end of the extended DEEP 2 enrolment, and the explosion in recruitment in recent months, ApoPharma has been asked to continue its supply of deferiprone to fund treatment of the many patients who still have only a little less than a year left on study. We have also been requested to cover the financial shortfall that is a natural accompaniment to this delayed take-off, and especially to help purchase deferasirox, the expensive comparator specified by PDCO.  We have agreed to both in the interests of everyone involved in the study, from scientists and investigators to the young patients”.

Regarding the application for Market Authorization in 2017, Dr. Spino explained that “assuming that the data reveal that deferiprone is non-inferior to deferasirox in this population, ApoPharma intends to file a Marketing Authorization for pediatric use in the control of iron overload in children.  A 2017 target is probably optimistic, with the last patient, last visit likely to occur after the end of the first quarter of that year, a huge quantity of data to review and evaluate, a substantial, submission-ready report to produce, and the PUMA itself to prepare. The many investigators involved in the study are of varied experience in the complexities of large GCP studies.  Questions, and the resulting delays, will be inevitable, but overcoming the challenges to complete this study will bring tremendous satisfaction to all participants. If the submission timeline extends into 2018 but its quality is commensurately increased, that is an acceptable trade-off. Clearly, the DEEP studies will be required for obtaining EU approval, but will constitute only part of the submission. We look forward to a joint meeting among PDCO, CHMP, DEEP and ApoPharma to understand what is needed, and how best to put it in place with minimum delay to obtain Marketing Authorization.“

We have further discussed with Dr. Spino the added value that the DEEP project can bring in terms of market impact and if it will provide a competitive advantage compared to the other chelators available on the market. He stated that “The DEEP-1 study has already provided unique information, i.e., that the pharmacokinetics of deferiprone in children and adults are comparable, and hence that doses on a per kg body weight basis can be standardized.  While this was anticipated, it had not been proven. DEEP-2, as the first RCT of deferiprone and deferasirox in children, is the second major contributor to advancing understanding of chelator selection in a paediatric population.  Although some studies have been conducted comparing the two oral chelators, there have been no large RCTs. If non-inferiority is demonstrated, then the confidence of clinicians to choose whichever chelator is most suited to a particular patient will be enhanced.  Greater freedom to prescribe optimal chelation therapy is good for the patients, and in the long run should benefit ApoPharma as well”.

DEEP-2 is, in fact, a multi-national and multi-center clinical trial involving not only a paediatric multi-ethnic population with different cultures, laws and children of different ages but also a rare and disperse population with different Rare Congenital Anaemia which has faced (and is still facing) several challenges in many countries, especially in the Mediterranean area.

We have discussed the Tunisian situation in performing a paediatric clinical study with Prof. Mohamed Bejaoui, the Principal Investigator at the Centre National de Greffe de Moelle Osseuse in Tunis.

“The Tunisian regulation allows to perform clinical trials in children since 2014, while prior to this date a special permission from the Ministry of Health had to be required before starting the trial. Today the clinical trials in children pose no administrative, regulatory or ethical problems and this is an important result that will pave the way towards a new era for clinical research in Tunisia, especially in paediatrics”.

Prof. Bejaoui  stressed the importance of participating in an international research network as DEEP, because it allows the sharing of high-quality and effective knowledge with highly experienced research teams and to learn more about best practices of clinical trials. The international cooperation in clinical research is also a way to encourage interdisciplinary participation in developing solutions through high-impact and mission-driven collaborations.

Considering that clinical trials cannot be conducted on patients without prior obtaining their written consent and the situation could be slightly more challenging when involving paediatric patients, whom consent is deputized the parents/legal guardians, we asked Prof. Bejaoui how the site manages the problem of consent.

“Informed consent is necessary before the start of the trial. At our Center, a long interview is conducted by the principal investigator and at least one of his associates with each family. Children are followed during all the clinical trial. We talk to the child about the disease, we explain the different treatments available for the disease, the drug under study, the conduct of the trial, monitoring practices, potential treatment complications and so on. The child assent is fully voluntary and without any constraints whatsoever and when we are sure that the child and his/her parents have understood what this trial is for and how it works, we do generally receive any opposition to the sign of the informed consent, thus allowing the recruitment of a large number of patients. In this context – he further explained – we would like to step forward at our center and take part in the recently launched QuBo (Quality evaluation of the informative booklets for patients involved in the DEEP-2 trial) study, aimed to Quality evaluation of the informative booklets for patients involved in the DEEP-2 trial aimed to test the efficacy of the informative materials developed within the DEEP2 clinical trial in order to evaluate the level of readability, clarity and intelligibility for each age group”.

What is the progress of the study that is to date in the last collection rush for most of the centres involved and which are its main progresses and achievements? We talked about them with Assoc. Prof. Antje Neubert from Universitätsklinikum Erlangen (UKER).

“The study has recently 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. To date we have enrolled 301 paediatric patients (92% of 328 patients) from 16 centres in 6 different countries. All centres put huge efforts into the data collection. This data are sufficient to provide a comprehensive safety profile of deferiprone treatment in children and adolescents within our defined sample size and set confidence interval.”

With reference to how the long-term study results will increase deferiprone post-marketing evidence, Prof. Neubert pointed out that “the latest product information of deferiprone states that insufficient data on safety and efficacy in children below 10 years of age are available at the moment. The results of the long-term observational safety study DEEP-3 will close this gap and provide valuable safety data for the treatment of transfusional iron overload in children and adolescents with beta-thalassaemia major“. She also explained that adverse reactions will be more predictable and monitoring for known adverse reactions in children will make the treatment safer in general.

Considering that the prospective arm of the study has been 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), she further clarified that “data collection is still on-going, but in 286 patients we already have the complete data set. Our participating investigators are doing their best collating all the requested clinical data. Nearly 60% of our enrolled patients started deferiprone treatment before the age of 10 years. This gives us good confidence that the generated safety data adds to the existing data from other clinical trials and observational studies. So far we collected about 423 adverse events which may or may not be related to deferiprone therapy. Of those, our adverse reaction assessment team already evaluated 134 events including 49 serious adverse events. The team found that 42 adverse reactions and 20 serious adverse reactions related to deferiprone treatment were found. These reactions  – she continued – comprise elevated liver enzymes, arthropathy and mild to moderate neutropenia. However, these are only very early results and we need to wait for the final results before drawing any conclusions about the safety profile of deferiprone in children.”