Encouraging prospects for paediatric drug development in Europe

In 1968, the American physician Harry Shirkey coined the phrase therapeutic orphans to indicate the severe lack of effective and documented medicines for children. However, it took many years for the United States to pay attention to the problem. This led to a series of legislative amendments, such as the act to modernise the Food and Drugs Administration (FDA) in 1997 and the FDA's Paediatric Rule in 1998. In 2002, the Best Pharmaceuticals for Children Act of 2002 authorised the FDA to request studies of approved and, or, unapproved paediatric indications. It stipulated that drug manufacturers with new drugs and new indications also had to investigate their value for children. In return, it became possible for the drug industry to extend their patents. In Europe, similar ideas were initially discussed within the scientific community. In 1997, the European Society for Developmental, Perinatal and Paediatric Pharmacology initiated a round table discussion with the Committee for Human Medicinal Products (CHMP) of the European Medicines Agency. This initiative was well taken by the CHMP which initiated the process towards the paediatric regulation. However, it took 10 years before the paediatric regulations were enacted in 2007 after numerous discussions between the Agency, the European Council, the drugs industry, the medical community and finally the European Parliament.1-3 The World Health Organization's 2007 Better Medicines for Children resolution supported the actions taken in the United States and Europe.4 The strong need for documented and safe drugs for children and young patients was also expressed in the United Nations’ Millennium Development Goals for 2000, in particular the fourth goal, which was to reduce the child mortality rate by two-thirds by 2015. There have been substantial improvements in this regard in several parts of the world, but the mortality rates are still particularly high in Sub-Saharan Africa and Oceania.5 The European paediatric regulations have led to positive developments. The number of new medicines and indications has increased in Europe, as have the percentage of clinical trials covering paediatric patients.6 Such changes have not been seen in Japan and Canada, where similar regulations are lacking. In addition, there has been an increase in the information available about drugs for children, as well as in the public and political awareness of the situation. On the other hand, there have only been a few initiatives that have explored the possibility of developing old and out of date patented agents and making them available as new and age-adjusted pharmaceutical formulations to obtain data protection for a 10-year period. Despite European and American efforts to provide better medicines for children, there are still major difficulties in performing regular paediatric clinical trials that support applications for marketing authorisation. There are a number of different reasons for this. First, academic and drug industry trial sponsors both have difficulties collecting enough data with competent investigators. However, there are few exceptions, namely when strong and functional international paediatric specialist organisations are active in the field of drug development. Second, there is a lack of capable clinical sites with local resources and appropriate staff educated in Good Clinical Practice. Existing sites are unevenly distributed across Europe. Third, the recruitment of patients available for studies of many paediatric diseases is insufficient. The article by Ruggieri et al in this issue of Acta Paediatrica7 is interesting and describes the availability of competent clinical trial sites in Europe. The survey was carried out by European Network of Excellence for Paediatric Clinical Research, commonly known as TEDDY. The survey was sent to 107 clinical centres in the TEDDY database and there were 63 (59%) responses from 11 countries, which is considered to be fair response rate for such a survey. It was not surprising that two-thirds of the responses came from the three most populated countries in the group, namely Italy, Spain and the UK, and that the majority were from hospital-based centres. The online survey included 60 questions that were selected to indicate four quality criteria. These included scientific experience, readiness to perform clinical trials and trial competence, such as information technology tools, monitoring and pharmacovigilance. They also included Good Clinical Practice and interactions with legal authorities. Most of the patients (84%) were included in academic trials, and the rest were involved in industry-sponsored trials. The results were very positive. Two-thirds of the centres had a specific clinical trial unit or employed a study coordinator. Half of the centres reported that they had at least one full time medical doctor, nurse, pharmacist, study coordinator and data manager involved in the trials. However, the questionnaire did not request information about the availability of professional clinical pharmacological support for trials, which is a key academic competence in the area of clinical drug development. The respondents were asked if 16 performance indicators existed at their site. More than 60% said yes to 13 of those and in six cases the positive responses were 84% or more. The overall impression from the study was that the countries that took part had high standards and competence in paediatric drug development. The authors claim in the title of their paper that there is a potential for Europe-wide trials, but there are reasons why their results should be interpreted cautiously. The respondents came from 59% of the sites in 11 of the 13 EU countries that are members of the TEDDY network and two-thirds originated from Spain, Italy and the United Kingdom. This may have introduced an element of bias since there are many European countries who are not represented in the TEDDY network. The responses probably reflected an à priori focus on paediatric drug development that had more to do with theoretical deductions than actual observations or experience. This factor was not discussed by the authors, but it does need to be borne in mind. It is promising that the European Union has implemented political and commercial measures to improve the possibilities, readiness and competence for smooth implementation of paediatric trials across Europe. These included the launch of the Collaborative Network for European Clinical Trials for Children consortium in 2018, which aims to improve the clinical trial infrastructure to facilitate the development of new drugs for children. The consortium is a private-public-partnership that comprises academic and industry partners and a multitude of affiliated partners from 19 member states. The key elements of the projects, which will run until the end of April 2024, are single points of contacts in each country, effective feasibility procedures, education in drug development and effective operational conduct. Last but not least the overarching ultimate aim is to make the European network sustainable through a take-over by appropriate stakeholders in the society. The prospects for children's self-evident rights to receive documented and safe medicines in the near future are very positive. And that is because of this background of legislative measures and substantial economic support for building networks and capacity for clinical trials. However, it is regrettable that it has taken more than 50 years to reach this point since we first heard about therapeutic orphans. The author has no conflicts of interest to declare. Anders Rane

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