Many of the medicines currently prescribed to children may never have been studied in paediatric populations, meaning that medicinal products are administered without precise information on dosage, potential toxicity and evidence of clinical safety and efficacy at the recommended dosages. The ERA-NET PrioMedChild (Priority Medicines for Children) is a network of eleven research funding organisations from different EU Member States working on the development of research around medicines for children. Under the umbrella of ERA-NET PrioMedChild, the national funding organisations of the Netherlands, Estonia, Finland, France, Great Britain, Italy, Latvia and Poland jointly provided funds in the order of €8 million to support the European call. The research projects were funded for three years in consortia with a minimum of three participants from at least three countries and a maximum number of 8 research groups. Regardless of its size, each collaborative consortium should have the optimal critical mass to achieve ambitious scientific goals and should clearly show the added value from working together. The ERA-NET PrioMedChild received €1.7 million from the European Commission's DG Research to set up the network and collaboration, but no funds for research. The Joint Call was funded out of national research budgets. Partnerships between research funding organisations seek to bring coherence and cooperation to national research programmes and policies on research for Priority Medicines for Children. PrioMedChild aims to contribute to ensuring more effective and safer medicines for children. At the end of 2010 seven projects were granted, the majority of which are directly related to the field of rare diseases and orphan drugs:
- New drugs for rare diseases: cost-effectiveness modelling in cryopyrin associated periodic syndromes
When a disease affects only a few individuals in any nation, it can be very hard to establish the cost-effectiveness of treatments. Traditional methods to assess cost-effectiveness cannot be used because of the low number of patients. Given that expensive medications such as biologics are showing promising results in some patients with very rare diseases, it is becoming increasingly important to obtain detailed information on as many patients as possible. This promising new international collaboration aims to develop a model to evaluate both costs and (long-term) benefits in an orphan group of diseases, cryopyrin associated periodic syndromes, also known as CAPS. The same model may be used in other very rare disorders. Just a few children each year are diagnosed with one of the CAPS, a group of diseases which have inflammation as their main characteristic. Lacking any reasonable trigger such as an infection, their bodies go into full-fledged inflammation mode, producing high fevers, joint pains, skin problems and many other symptoms. In more severe cases, each attack causes damage to the brain and sensory organs, resulting in intellectual deficit, deafness and blindness. "The cost of illness can be very high in these patients, both in financial terms and in terms of their quality of life," says Genovese clinical pharmacologist Dr. Ornella Della Casa Alberighi, co-coordinator of the RaDiCEA (Rare Diseases & Cost-Effectiveness Analysis) project. (Learn more)
- Rare diseases: use of clinical trial simulation for the choice and optimisation of study design
Computer modelling can be used to find the best method of performing a clinical study on a new drug. Finding the optimal study design is especially important when testing drugs in children with rare diseases, to minimise the research burden on young patients and optimise the chances of finding effective and safe treatments. Like any other drug, orphan drugs must be tested to make sure they are effective and safe, before being authorised for use on the European market. This can be difficult, because the low numbers of patients with rare diseases may not allow for the traditional model of clinical drug trials, the randomised controlled trial (RCT) in which patients are assigned at random to a study group or a control group. Statistics show that to achieve results with sufficient certainty, relatively large groups of patients are needed, often as many as several thousand. So what can be done when there are not that many patients? Will another study design predict efficacy and safety with an acceptable amount of certainty? Can it be determined in advance which study design provides the best guarantee that a trial will produce reliable results? Computer modelling may prove to be the essential tool here. This PrioMedChild project tries to find new methods of studying the safety and efficacy of drugs, in a more tailor-made fashion. Dr Catherine Cornu, who coordinates the project along with her colleagues at Université Claude Bernard (Lyon), Dr Patrice Nony and Dr Behrouz Kassai, explains, "We want to develop a model that will enable us to say: if you have this disease, and this drug aimed at this particular mechanism, then this is the study design for you. Ideally, the model would predict the best study design for any disease, but that may take many more years of research. What we do in this project will be the first steps towards that goal". Researchers from several European universities are working together within the project. They combine expertise in mathematical models, biostatistics and clinical drug trials with specific knowledge about three rare diseases: severe myoclonic epilepsy in infancy (Dravet syndrome), cystic fibrosis and lymphoblastic lymphoma. In the initial stages of the project, the researchers will aim for specific clinical targets, such as prevention of pulmonary complications in cystic fibrosis. Says Dr Cornu: "To develop our methodology, we need to focus. At first it will be one drug, with one purpose and one endpoint we can connect to our disease model. With all that in place, our group can then make a computer model to design the best clinical trial. We can simulate thousands of clinical trials with different designs and compare results: which design yields the highest precision with the shortest duration and the lowest number of patients? In these rare diseases, there is no second chance to get it right in reality, so a computer simulation can help you prepare the best possible study and give drug trials the best chance to arrive at conclusions". (Learn more)
- A faster and better tool for clinical decisions in children with leukaemia
Minimal residual disease (MRD) has become a key phrase in treating leukaemia. The number of cells still within the bone marrow after an aggressive course of cytostatic treatment has been shown to be a crucial predictor of outcome. If no cells can be found, a milder treatment regime is possible. New techniques have been developed in the laboratory to measure MRD faster and more precisely. Now, via the PrioMedChild programme, they are to be tested in a multi-centre European study. Should it succeed, clinicians will have better tools to decide on the dosage of medication and the use of very expensive new medicines. Treating children with leukaemia is notoriously difficult. There are several effective cytostatic drugs, but they are also highly toxic. If the child receives too little of this medication, the disease bounds back with a vengeance. But the price of survival may be high, as there are often late effects on heart, bones, kidneys, skin and brain. During treatment, it would ideally be possible to know which children will need high doses of cytostatic drugs and who may be cured with lower doses. This has been the aim of scientists for quite some time. Explains Prof. Dr Jacques JM van Dongen of Erasmus University Medical Centre in Rotterdam: "We started to work on this subject in the 1980s, and it took us more than ten years to develop sufficiently sensitive techniques for detection of low frequencies of leukaemic cells. What we did find already, is that the number of leukaemic cells in the bone marrow after the first course of treatment, the minimal residual disease, MRD, is crucial for prognosis. If we cannot find any leukaemic cells, the disease returns in only a very few patients. In an intermediate group, where one in 1000 to 10,000 cells is malignant, the relapse rate is about 25%. With more than one in 1000 cells, there is a very high chance, about 80%, that the leukaemia will come back. We also knew from the 1970s, that low doses of chemotherapy were able to cure 35 to 40% of all children with leukaemia. So we wondered: maybe the patients in whom we could not detect any residual leukaemic cells are the ones who do not need high doses of chemotherapy? When we put this idea to the test, experts from other countries predicted disaster. But we now have more than 500 children included in our MRD study, and we proved that it is safe to leave out the intensive second course of treatment in those children who have no MRD". In the PrioMedChild project, van Dongen and his colleagues from Poland and the Czech Republic will test an approach based on recognition of protein molecules on the cell surface, the so-called 8-color flow cytometry. "Using newly developed flow cytometry software with a special statistical technique known as principal component analysis, we can recognise leukaemic cells. We use eight slightly different surface characteristics, combining them in such a way that they yield almost one hundred percent certainty". The new technique has already been tested in the detection of leukaemic cells in high concentrations. The challenge will be to show that it also works to detect 50 leukaemic cells among half a million healthy ones. "It is the proverbial needle in the haystack," van Dongen admits. "New drugs are being introduced, many of them biologicals based on antibodies against cancer cells. A sensitive and specific test for MRD may help to identify those patients who have the highest risk with conventional treatment and who may benefit most from these expensive drugs. Another great advantage will be that we collect all the primary data in all the participating centres. Because of the high levels of standardization, we can combine the primary flow cytometric data into one data base, making further scientific progress a lot easier. I think it is really fantastic what this PrioMedChild grant allows us to do". (Learn more).
- Developing an effective treatment for childhood cancer with fewer side effects
Chemotherapy is frequently effective against childhood cancer, but there can be severe side-effects. Treatment may have lifelong negative consequences, because of damage to developing tissues and organs. A research team from several European countries is currently seeking a 'golden bullet' technology which will deliver drugs directly into cancer cells, thereby sparing healthy tissue. Using nanoparticles and several methods to ensure specific targeting of cancer cells, the teams hope to improve drug delivery and timing, prevent overdosing and overcome drug resistance. The researchers already have extensive experience in the use of so-called biomaterials, compounds that can be safely used within the human body. They propose to use a combination of two biomaterials (chitosan and polypyrrole) to create microscopic balls (nanospheres) containing an anti-cancer drug. Creating these nanospheres will be the task of the Paris group. These nanospheres are closed, so that toxic drugs cannot escape and damage healthy cells. The next stage in this PrioMedChild project, carried out by an INSERM team in Toulouse will be to check, by employing imaging techniques, that the drug actually remains within the little molecular balls. To unlock the nanospheres, a chemical trigger is needed, such as the amount of acid in the environment. It is a known fact that cancer cells produce more acid than normal cells. The researchers hope to utilise this property, developing new biomaterials from the combination of chitosan and polypyrrole that change their structure when they enter the acidic micro-environment of a tumor. This change opens the nanosphere, releasing the drug. To enhance selectivity of the drug delivery process, nanospheres which carry specific receptors will be developed. They will function as specific triggers to open the nanospheres. (Learn more).
The other projects of the PrioMedChild network will look at Validating non invasive imaging of the serotonergic- and dopaminergic system and adult neurogenesis with MRI; towards a better insight in the neurobiological mechanisms underlying psychiatric disorders in the paediatric population; Paediatric Accelerator Mass Spectrometry Evaluation Research Study; and Neonatal Exposure to Excipients. These seven projects contribute to making medication use safer for paediatric populations, including children with rare conditions.
Visit the PrioMedChild website