Session II

MANAGEMENT OF THALASSAEMIA AND HAEMOGLOBINOPATHIES: AN ONGOING CHALLENGE

Deferiprone investigational pathway: beyond thalassaemia and haemoglobinopathies by Michael Spino, President of ApoPharma Inc., Canada

The use of deferiprone (Ferriprox) in thalassemia was originally employed to reduce the body’s burden of iron.  When a decline in heart disease and an increase in survival were detected, it became apparent that deferiprone was doing more than removing iron from the body. The effects of deferiprone in moderating the damage of labile iron on mitochondria was seen as a key.  Based on this understanding, and the awareness that dysfunctional processing of iron occurs in several neurodegenerative conditions, ApoPharma explored how deferiprone might alleviate the pathological contribution of malfunctioning iron homeostasis in inherited neurodegenerative conditions, like Friedreich Ataxia and Pantothenate Kinase-associated Neurodegeneration as well as neurodegenerative conditions that evolve later in life, like Parkinson’s disease and Alzheimer’s. Interestingly, in all of these conditions, malfunctioning mitochondria are a prominent component of the disease.  Our current view is that deferiprone’s effect on the mitochondria and its effects on a series of cytokines and genes that control them are as much a contributor to the favourable outcome in animal models and human studies of neurodegeneration as is the reduction of ROS-mediated damage from the chelation of excess labile iron in the cell.

Model-based evaluation of benefit-risk balance in chronic iron overload in children by Prof. Oscar Della Pasqua, Chair of Clinical Pharmacology and Therapeutics, University College London, United Kingdom

Aims: Here we illustrate the advantages of applying multicriteria decision analysis (MCDA) in conjunction with PKPD modelling to assess long term benefit-risk balance of iron-chelation with deferoxamine.

Methods: Clinical data from a small cohort of -thalassaemia patients undergoing treatment with deferoxamine were modelled along with literature findings on iron overload in the same population. Using the models obtained for five different endpoints, clinical trial simulations and not-in-trial simulations were performed to characterise the benefit-risk profile in a virtual cohort of paediatric patients. A range of dosing regimens was evaluated, including weight-banded and ferritin-guided individualised regimens.

Results: The results of the MCDA show that benefit-risk balance can change considerably over time. Differences in the pharmacokinetics and pharmacodynamics of children below 20 kg and in patients with serum ferritin levels below 2500 µg/L suggest that these subgroups may benefit from alternative regimens.

Conclusions: Our analysis shows the feasibility of integrating PKPD relationships into benefit-risk methodologies, allowing for a more systematic assessment of the BRB of a medicinal product in children. Of relevance for paediatric diseases is the possibility to evaluate BRB beyond the duration of treatment.

Treatment and care organisation for SCD: a new challenge in Europe by Dr.Paul Telfer, Queen Mary University of London, Barts Health NHS Trust, United Kingdom

The prevalence of SCD in Europe is increasing as a result of immigration, particularly from Sub Saharan Africa. Health care services need to take account of the changing epidemiology and ensure that care programmes are implemented which reflect the medical, psychological and social needs of the patients. Accumulating evidence justifies the inclusion of a range of components in care programme, each of which presents different challenges. Examples include newborn screening, transcranial Doppler screening for stroke prevention, specialist care for acute and chronic pain management, therapies such as hydroxycarbamide, simple and exchange blood transfusion and allogeneic bone marrow transplantation, psychological and social support.

A favoured model for comprehensive care delivery is a regional network incorporating specialist centre, local centres and community care. Continued Education and training of medical, nursing and allied staff, engagement of patients and integration into the primary secondary and tertiary health care structure are all needed to ensure that care is effective, safe and acceptable. The NHS in England is evaluating haemoglobinopathy services by use of Key Performance Indicators, mandatory audits, and peer review of centres. Some of these metrics may also be appropriate for other countries in Europe.

Patients Registries at National and International level  by Alessia Pepe, MD, Ph.D, Cardiologist and Radiologist, Magnetic Resonance Imaging Unit, Fondazione G. Monasterio C.N.R.- Regione Toscana, Pisa, Italy.

Rare disease patients represent a ‘small population’  where  the challenge is to collect evidences to improve the management.

One of the instruments to overcome the limits about the research on rare disease is to collect non sperimental data from registries.

Public Health authorities collect data by regional and national population-based databases which refer to a geographically defined population and aim to register all cases in that population.

Conversely, non-population-based registries are based on clinical centers or other criteria (members of scientific society or  patient organization, or other disease-specific registry) where the population coverage may not be comprehensive.

Disease registers collect homogeneous data, they  assess specific outcomes, and answer to specific clinical issues by  improving the health of the patients. They represent key tools to increase knowledge on rare diseases.

In the European Region no more of 13 out of the 34 member countries have registries for haemoglobinopathies. In Italy there are at least 3 disease registers. It is recommendable to push  these data base working together. Going in this direction MIOT and HTA-Thal are building an agreement to work together. This effort it is strategic in the ongoing phase of the call for European Reference Network (ERN) where funding for rare hematological disease  should include support for registries and networking.

The relevance of genetic prevention for Haemoglobinopathies by Marina Kleanthous, Head of Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics; Associate Professor, The Cyprus School of Molecular Medicine, Nicosia, Cyprus

Prenatal diagnosis (PD) for monogenic diseases is mainly based on the analysis of chorionic villi sampling (CVS) or amniotic fluid using PCR based techniques. Recent technological developments pose new challenges in the field. The use of high-throughput NGS and bioinformatics tools will have tremendous implications in PD.  Early knowledge of the genomic background of the patients will result in a more accurate prognosis of the disease, the application of personalized treatments while it is expected to affect prevention approaches and genetic counseling. Another approach used in PD for haemoglobinopathies is the Preimplantation Genetic Diagnosis (PGD), a method that ensures the transfer of healthy embryos in the uterus avoiding thus the selective termination of an affected pregnancy. A more recent approach in PD that is based on the analysis of cell-free fetal DNA in the maternal plasma is the non-invasive prenatal diagnosis (NIPD). Currently, NIPD is routinely applied for aneuploidies, for the determination of fetal sex in pregnancies at risk for an X-linked disorder and for the fetal Rhesus D (RHD) status in pregnancies at risk for hemolytic disease of the newborn but is under development for single gene disorders.

Steps towards an international Network in Paediatric Haematology by Prof. Adriana Ceci, DEEP Scientific Coordinator, Scientific Director of Consorzio per Valutazioni Biologiche e Farmacologiche, President of the Gianni Benzi Pharmacological Research Foundation, Italy

Following the entry into force of the Paediatric Regulation, EU paediatric networks gathered in EnprEMA, the European Network of Paediatric Research at the European Medicines Agency, to foster high-quality ethical research on medicinal products in children. The adhesion to EnprEMA is subsequent to a self-assessment procedure.

To date, EnprEMA includes in this area only the Paediatric Diseases Working Party as subgroup of EBMT (European Blood and Marrow Transplantation), while a specific Paediatric Haematology Network is not included.

The DEEP consortium is entitled to promote this international network in Paediatric Hematology intended to be part of EnprEMA, based on the achievements and progress made in these years and in particular on:

• the harmonisation of clinical and diagnostic standards for trials in thalassaemia/SCD patients in a large geographic area including Mediterranean area.
• ability to fulfil GCP requirements for paediatric trials improving the quality and aligning the services, standards and procedures offered by each centre.

Expected advantages. The Network could candidate in the ongoing EU initiatives, such as the Paediatric Research Infrastructure, to be part of the future pan-European Paediatric Clinical Trials network (EUPCTN), and to have access to public and private funds.

Session I

CHALLENGES AND OPPORTUNITIES OF CONDUCTING CLINICAL TRIALS IN PAEDIATRICS

Clinical research: where are we now with the new CT Regulation by Prof. Hugo Devlieger, DEEP Ethics Board Member, Department of Development and Regeneration, University of Leuven, Leuven, Belgium

The new European regulation on clinical trials was adopted in May 2014 and was supposed to enter into force by May 2016. This regulation is intended to abolish Directive 2001/20/EC and correct some of its shortcomings e.g. the lack of harmonization, and hence its attractiveness especially for multinational trials. Central to this harmonization process is the registration of the CTA in a unique EU portal, set up and managed by EMA, and that will function as a communication center between the sponsor and the MS. The risk based approach led to the differentiation between CT and low-intervention trial requiring less stringent demands. Other important changes are the co-sponsorship and the short timelines. The sponsor has to register the trial in the EU portal together with the EU medicinal product number and propose a reporting MS that will assess the scientific part of the application while other MS interact or tacitly approve The informed consent process is still assessed by each MS but within the same short timeline. The regulation takes into account a great number but not all of the EC Paediatric Recommendation (2008). Due to delay in the development and agreement of functionality of the EU portal, the new regulation will not enter into force before October 2018. In conclusion, only the implementation of the new regulation, intended to harmonize and coordinate, will learn us if it holds its promises and lead to improve the quantity and quality of CT in children without bending the ethical principles.

Challenges and new opportunities of cooperation with the Mediterranean countries in the field of paediatric clinical research by Prof. Amal El-Beshlawy, Professor of Paediatric Hematology, Cairo University, President of the Egyptian Thalassemia Association, Egypt

Research is a complex process, generation of knowledge is only one part of the research process, for knowledge to be useful it should be shared with other researchers in different nations and communities. The EuroMediterranean network of research centers of thalassaemia and other haemoglobinopathies is a good example for enhancing the scientific potential for a high impact collaborative research in Egypt and other Mediterranean  countries. Infrastructure for thalassaemia research network (ITHANET) and the Euro-Mediterranean Network for Genetic services (MedGeNet) were a good example for constructive and beneficial collaborative work in the domain of medical management and diagnostic skills for haemoglobinopathies. The DEEP Project (FP7) is a new aspect of Euro-Mediterranean collaborative study for the development of an old drug in a new liquid formulation specific for the pediatric population with haemoglobinopathies.

Although we have some challenges in the research studies in Egypt, we have got many advantages: a huge population with many diseases diversity; big pool of treatment naïve subjects; university hospitals with a strong infrastructure and facilities; GCP compliant regulators and Ethics Committees; no regulatory limitations on pediatric researches and highly qualified investigators with international accreditations.

The Ethical issues in EU and non EU countries by Viviana Giannuzzi, Researcher and regulatory expert at the Gianni Benzi Pharmacological Research Foundation, Italy

From the ethical point of view, paediatric research looks for the balance between protecting children while making sure they benefit from safe and efficient medicines. The complexity increases because paediatric studies are typically multi-centre and multi-national, and ethical requirements differ among countries and national legislative frameworks.

This has been highlighted both at international and European level, where Directive 2001/20/EC, guidelines and recommendations have been differently implemented in national laws. The upcoming European Regulation 536/2014 is expected to harmonise practices in Europe and possibly outside Europe.

In the framework of FP7 programme, many paediatric multi-national trials have been funded and faced the challenges related with the multi-ethnicity of trial populations and the need for complying with GCP and ethical standards guaranteeing children’s protection. Most of them have been already approved by the local ethics committees and are ongoing all around Europe and outside.

Today, many clinical and therapeutic information from paediatric patients are obtained from the secondary use through the retrospective collection of ‘big data’. This is requiring greater and greater effort to guarantee an ethical standard for children, protection for confidentiality and personal data, including genetic data, given that the ethical framework in this field is less regulated.

Global initiatives for paediatric research: the path to the European Paediatric Clinical Trials Research Infrastructure (EPCTRI) setup by Donato Bonifazi, Chief Executive Officer at Consorzio per Valutazioni Biologiche e Farmacologiche, DEEP Project Manager

A Research Infrastructure is a research tool identified in the European Research Agenda with reference to facilities, resources and related services used by the scientific community to conduct top-level research in their respective fields. Unlike the clinical research landscape in adults, there is no commercial or academic research infrastructure to efficiently perform paediatric clinical research. This is due to the well recognised difficulties in developing paediatric medicines as children cannot be addressed with adult instruments in medical settings. In March 2015, a large group of top level research networks located in several European countries, led by the ENPR-EMA Co-Chair Prof. Mark Turner, developed and submitted a proposal to build an infrastructure addressing this gap all across Europe with innovative scientific and methodological strategies.

This new research infrastructure, named EPCT-RI (European Paediatric Clinical Trial – Research Infrastructure) will include many therapeutic expertise over a broad spectrum of disease indications and conditions as well as innovative research methodologies.

Expected results: EPCTRI will enable researchers to manage paediatric clinical research and implement important research activities through the creation of innovative platforms and will bring many advantages: aggregation and growth of scientific structures in the field of innovation and life sciences; development of new medicines for children to enhance their health, safety and quality of life; promotion and development of new business and industrial processes.