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It’s called STAND4Kids –Supporting Pediatric Trials in Portugal – and it is the national face of the Conect4children (C4C – European Clinical Trials for Children)consortium, a European network financed by Innovative Medicines Initiative whose main purpose is to improve the infrastructure for paediatric clinical trials and facilitate the development of new medicines for children. The purpose of this Portuguese hub, STAND4Kids, is to support academic and clinical research in this area, working together with centres, health professionals, children and their families.

The person who is leading this project was not chosen at random: Paediatrician at the Santa Maria Hospital, working in the respiratory tract and allergy area, Professor Ricardo Fernandes is also developing research in Clinical Pharmacology.

A former student of the Faculty of Medicine of the University of Lisbon, he completed his General Internship at the Garcia de Orta Hospital, returning to Santa Maria to complete his degree and, later on, to work in his speciality. Doing research for more than 10 years, he says that his main academic interests are Clinical and Therapeutical Pharmacology, coordinated by Professor Joaquim Ferreira, and Paediatrics, currently led by Professor Ana Isabel Lopes. Initially, when he considered his options, he thought about Neurology, challenged at the time by Joaquim Ferreira for a joint project, but he ended up following a different path. Years later, their paths crossed again, leading them, one way or another , to work within the scope of shared interests, which include methodology and Clinical Pharmacology. It was after a spending some time between the Netherlands and Canada and also by influence of his clinical mentor, Professor Teresa Bandeira, that Ricardo Fernandes eventually decided that his PhD would be about bronchiolitis, a common, acute respiratory illness with a significant short- and long-term impact.

It was also at this point in his life that he came closer to research in paediatric clinical trials. He first came into contact with this area through StarChild Health, an international initiative focused on the paediatric particularities of studies in children, led by Martin Offringa, a Dutch paediatrician and researcher who was one of this doctoral advisors. He strengthened that contact getting involved in Cochrane Child Health and various methodological evidence synthesis projects. A decade later, and despite the fact that obstacles are proportional to the capacity for intervention, he decided to embrace the coordination of STAND4Kids and create the conditions to simplify research dynamics. It was becoming increasingly important to understand how to get the paediatric community involved, because no networks had yet been established in Portugal and there wasn’t, and isn’t, a strong tradition of clinical research in paediatrics, particularly in clinical trials. The Portuguese Paediatric Society brought together all the leading figures in this area, and that’s the reason why it was involved in this project.

At a stage where there is still little scientific evidence and limitations in paediatric medication, it is necessary to understand the risks and benefits of the existing drugs and, in particular, how clinical trials could be the right tool to bridge these gaps. Professor Ricardo Fernandes emphasised the starting point for the project, “Paediatrics knows what it’s doing, but if we’re thorough, it does it with very little information“.

In view of the lack of evidence and the few clinical trials, there was the need for a new approach for designing them, conducting them, and reporting back to the community. The fact that trials designed for adults are often not directly applicable to children was anticipated as one of the major challenges that would be faced in this area. But the design of trials has particular constraints, as Ricardo Fernandes explains. For example, “In Paediatrics there are situations where the number of children who have a certain pathology is very small. This raises specific challenges when it comes to the way we scientifically design the trials, how we implement them, how we select and analyse their outcomes and results, how we get the patients involved in all these processes, and that’s one of the key points”. And while in some countries efficiency in conducting trials is already being shown by paediatric networks with good performances, “Portugal is still one of the few countries that doesn’t have this type of network in place.”

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The sum of all these fragilities gave rise to Conect4children, focused on the real applicability of Science, on a country-by-country basis. Launched in May 2018, it has the characteristic of being financed by both the 2020 Horizon Research and Innovation Programme of the European Union and by the European Pharmaceutical Industry, while relying on the collaboration of university partners and research networks. It will last for 6 years. “The goal is to create a European clinical trial network“. The idea of a “one-stop shop” that allows the promoters of studies or researchers who want to develop or implement a clinical trial project to have a “Single Point of Contact/SPoC” with the appropriate coordination. That will allow promoting the access to experts in the area of paediatrics and methodology, the involvement of youth groups and families, and the role played by networks at the national level, contributing to the design of the study and to the assessment of the feasibility of the project. If feasible, the project can then be implemented by the European network, supported by its national Hubs, with standardised processes and according to the best clinical practices. Lastly, the entire process will be monitored to become efficient.

The Conect4children is a collaboration between the academic and the private sectors, includes 33 academic institutions, 10 industry partners from 20 European countries, more than 50 third parties, and nearly 500 affiliated partners.

Currently coordinated by an Italian team, the European consortium establishes a point of contact with the national Hub STAND4Kids, managed by the AIDFM (Association for Research and Development of the Faculty of Medicine), a non-profit association of public interest that promotes biomedical research at the Faculty of Medicine of the University of Lisbon and is the Portuguese beneficiary of the programme.

Between meetings, Ricardo Fernandes outlines a communication plan and defines priorities with Maria Inês Simões, a graduate in Nursing with experience in the Paediatric area who is coordinating the project. The team at AIDFM-CETERA (the department responsible for managing the project) integrates Inês Cabrita, Chief Operations Officer, Francisca Figueiras, Scientific Affairs Manager, and Maria Fátima Casaca, Financial Assistant at the AIDFM. We also talked about the current scenario in Portugal and the barriers they face in attaining a dream that is starting to come true.

How do you do clinical trials in a group as delicate as children? Is it the same as doing trials in adults?

Ricardo Fernandes: There are several aspects we need to address, because within the spectrum of Paediatrics it’s very different dealing with a premature baby, a new-born and then an adolescent. Then we’re not just talking about trials that will give answers for treatments; a good example of that are the vaccines, which are preventive. Clinical trials are not only focused on children who are already ill, and they can be aimed at very different purposes, from drugs, to medical devices or even neuropsychological interventions. Traditionally, it is easy to follow the reasoning that says, “be careful with children, be careful with infants, they are particularly fragile”. But there are many situations where it is legitimate to carry out randomised trials because it is the most valid method to find an answer to the scientific question “how efficient and safe is this intervention?”, naturally respecting basic ethical principles. But there is another side to the coin, for example, when dealing with an extremely premature baby to whom I’ll have to give a variety of drugs in the first few days, what is the basis of science to support immediate and long-term benefits and risks? Sometimes it’s very low and we make off label choices, i.e., outside the approved indications.

Does this mean that experience prevails over scientific evidence?

Ricardo Fernandes: It is experience that often dictates your decisions when dealing with children, but we need good science to support them. Maybe it’s professional bias, but I believe that those who work in paediatric care have specific characteristics. Paediatricians, nurses and so many other health professionals dedicated to this area are very concerned and available to follow up and understand what is going on with children and their families. And it is this sensitivity that allows them to interact differently with the little ones, but also with their parents. Contrary to some opinions, I think that parents are not that complicated. Their perception of the child’s problem is as crucial as that of the professional. In research we also need to work together with professionals and families. From the scientific point of view, there are enormous challenges when it comes to measuring and analysing aspects that allow us to characterise and compare the effects of tests or therapies on children. A professional with less experience doesn’t have the same perception of the child as one who has an extensive experience which allows him to reach more comprehensive conclusions, sometimes difficult to quantify scientifically. Despite the fact that much work has been developed for example in the area of paediatric outcomes, there is still a lot of room for improvement in clinical research in this area.

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How do you reconcile clinical activity with research in a country that doesn’t have the appropriate regulations for that purpose?

Ricardo Fernandes: More than 10 years ago, I joined the first year of a Doctoral Programme that was a partnership between the Gulbenkian Foundation and the Champalimaud Foundation, with other support – the Advanced Medical Training Programme. It was a pioneering initiative, led by Professor Leonor Parreira, and intended to contribute to address the shortage of medical researchers. There is always a degree of exception to the rule and risk in someone who gets involved in these two scenarios at the same time. I did the PhD in part-time and only interrupted my clinical activity on a few occasions. What I want to say is that nothing is easy and that the issued has been discussed for decades, with relevant but very gradual gains. Actually, I was probably the first person to benefit from the Intern Doctoral Student Status in Portugal, which allowed me to do my PhD while working in the clinical and assistance areas. Many of my Doctoral Programme colleagues chose to stay abroad and built great careers. In initiatives such as the GAPIC Research Day we’ve been trying to bring some of them to the FMUL. I can tell you that, 10 years later, things have improved, there are more opportunities and conditions, but there is still a long way to go to achieve more openness to high-quality medical-scientific careers, that will allow us to deal with the increasing pressure from the point of view of assistance, but also to be demanding when it comes to the production and impact of research. Part of the problem has to do with framing and asserting those careers in a real context of a growing number of appointments, pending procedures and interventions, emergency rosters that need to be filled… And I should point out that assistance needs are absolutely legitimate, and that the quality of care must be at the heart of good clinical research. For this project, it was crucial to have time. Interestingly, the Direction of the FMUL joined the project as third-party and welcomed it. I would like to thank the Lisboa Norte Hospital Centre, particularly the Director of the Medical Paediatrics Service (Dr. Celeste Barreto) and the Head of Department (Professor Dr. Ana Isabel Lopes), the Clinical Direction, and the entire team of the Allergy Unit (coordinated by Professor Ana Neves) and my colleagues for letting me follow this path at this stage.

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At the beginning of April, the key members of the European consortium met in Portugal to determine which academic clinical trials will be funded. After that meeting, each national hub will meet and define strategies with a more local nature. Portugal is intending to participate in 2 or 3 academic clinical trials and another 2 or 3 with commercial promoters, supported by c4c.

In these 6 years, STAND4Kids intends to create a network of partners and contacts that will allow its medium- and long-term sustainability. The aim is to create a structure to properly promote and consolidate paediatric research among the professionals, and one of its key aspects will be to strengthen the bonds of trust with the families of the children who will be involved in this project.

Joana Sousa

Editorial Team