19.07.2019 | Christina Bucci-Rechtweg, Global Head, Paediatric & Maternal Health Policy, Regulatory Affairs, Novartis Pharmaceuticals Corporation
The Nordic Contribution to Delivering Better Medicines for Europe’s Children
The paediatric population is primarily healthy, rendering paediatric drug development research challenging due to the limited number of children typically impacted by a medical condition.
Traditional drug development approaches using large randomized controlled trials to evaluate a drug’s benefit and risk profile are rarely an option. This challenge is further complicated by the additional need for developmentally-appropriate outcome measures for children across the age spectrum, adaptations required in research procedures and settings to accommodate children's physical, cognitive, and emotional development, as well the need to comply with ethico-legal protections due to their vulnerability.
These complexities, in addition to the lack of commercial drivers, have led paediatric drug evaluation to be neglected historically, leading to inadequate efficacy and safety information for drugs frequently used to treat childhood diseases. Over the past two decades, governments have been addressing the inadequacy of drug testing and insufficient information for use in product labels for children through the introduction of policies intended to stimulate investment in pediatric drug development. In the United States and Europe, these laws have been impactful tools to enhance both the quantity and quality of medicines development for children.
In Europe, it has been over 10 years since entry into force of Regulation (EC) 1901/2006 (“Paediatric Regulation”). The Paediatric Regulation requires drug developers to provide a paediatric research plan to evaluate each new regulatory submission of a new indication, formulation or method of administration for its application to paediatric populations. Therefore, the primary approach to paediatric medicines development is through the evaluation of medicines that have been identified as assets due to other disease or marketplace drivers (e.g., adult diseases). One of the important achievements of the Paediatric Regulation is that drug developers are now routinely assessing their drug development portfolios to identify how to efficiently and effectively integrate paediatric considerations into the adult medicines development program. As of 31 December 2017, more than 1000 Paediatric Investigation Plans (“PIPs”) have been agreed by companies in compliance with the Regulation, of which 150 have statements of compliance included within a marketing application (MA).1
To facilitate paediatric drug development, there has been significant investment into the development of infrastructure to accommodate and address the unique needs of children throughout the development and life-cycle of a product. Researchers, institutions, regulators and the regulated drug development industry in the Nordic region have been instrumental in ensuring that paediatric populations from within the countries and associated territories contribute to the shared knowledge gained through research and evaluation of new therapies for children.
On review of public databases, Denmark, Greenland, the Faroe Islands, Finland, Iceland, Norway and Sweden all have investigators or institutions who are participating in ‘Industry-sponsored’ phase I, II, III or IV trials that are “Recruiting”, “Planned - Not yet recruiting”, “Active - Not recruiting” or “Enrolling by invitation”. As of 25 June 2019 (https://clinicaltrials.gov/), Sweden leads the Nordic region with 109 ongoing studies (including paediatric populations) that are evaluating therapeutic outcomes with either investigational or approved therapies. In addition, the Nordic region has established itself as a leader in the field with the establishment of successful and active paediatric research networks including FINPEDMED - Finnish Investigators Network for Pediatric Medicines, and the NorPedMed – Norwegian national multi-specialty Pediatric Network, whose aims are to develop new innovative approaches to facilitating the successful execution of paediatric clinical studies.
Delegates to the EMA’s Paediatric Committee (PDCO) have been influential in shaping regulatory thinking related to paediatric research plans for PIPs. From 2008 through 2013, the Norwegian Medicines Agency’s delegate also served as the Chair for the PDCO’s Formulation Working Group. The oversight of this working group has been essential to ensuring that requirements for age-appropriate formulations will allow for the accurate, safe, palatable and acceptable administration of medicines to children of a wide range of weights and with a wide range of developmental characteristics.
A primary tenet of the Paediatric Regulation is to avoid subjecting paediatric patients to unnecessary trials. The limited paediatric patient population affected by certain diseases and the complexities introduced when multiple drugs each have a commitment to conduct paediatric studies greatly diminishes the feasibility of conducting a paediatric study. However, research from adults cannot simply be generalized to neonates, infants, children, and adolescents. To address this, experts have been actively discussing how to utilize pre-existing knowledge to facilitate the evaluation of age- and development-dependent changes and their pharmacokinetic or pharmacodynamic impact in order to facilitate our understanding of the applicability of a drug for a paediatric population. This commitment to the application of methodologies including model-informed drug development (MIDD) and paediatric extrapolation to facilitate the use of pre-existing knowledge will enhance design considerations for pediatric populations. The Medical Products Agency in Sweden has been active in providing paediatric pharmacometric review and consultative expertise through the Modelling and Simulation Working Group of the EMA and through its delegate’s contribution to the ICH E11A Expert Working Group as they development a guideline on Paediatric Extrpolation that will have global implications for paediatric medicines development.
The pharmaceutical industry is at its core an innovation sector. In the modern era, development of new medicines has positively impacted the quality and duration of human life like never before. The industry has been highly successful at identifying and developing novel assets where no prior treatments existed by focusing on the intersection of unmet medical need and scientific tractability. The introduction of the Paediatric Regulation in Europe has been pivotal in cementing a commitment to improving paediatric patient outcomes across the pharmaceutical industry in particular for those adult medicines which may have a role in addressing paediatric needs.
As drug developers have gained paediatric drug development experience, they have begun to translate and apply their knowledge to investigational drugs designed to address diseases observed primarily in paediatric populations. Pharmaceutical industry pipelines now include highly targeted therapies and utilize precision medicine approaches that take into account genetic variability, environment and lifestyle to treat or prevent disease. While these new products for paediatric use represent only a portion of all new drug and biologic approvals, the investment despite disease complexity, scarcity of available patients, and modest commercial upside in relation to adult marketplaces, reflects an important shift in understanding the value of medicines development for paediatric patients. This expands the traditional paediatric medicines development landscape and opens even broader opportunities for contribution from the Nordic paediatric research infrastructure.
Taken together, the commitment of the regulated pharmaceutical industry to paediatric medicines development all-the-while leveraging the Nordic experience and potential, will vastly improve the environment within which the medical needs of Europe’s children are addressed.
1 EMA Report to EC (2017). Published 25 Apr 2018. EMA/6652/2018.
Christina Bucci-Rechtweg, MD, Global Head, Paediatric & Maternal Health Policy, Regulatory Affairs
Novartis Pharmaceuticals Corporation