European regulatory strategy for supporting childhood cancer therapy developments.

INTRODUCTION: Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs. OBJECTIVE: Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development. CONCLUSION: An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings.

The benefits, limitations and opportunities of preclinical models for neonatal drug development.

Increased research to improve preclinical models to inform the development of therapeutics for neonatal diseases is an area of great need. This article reviews five common neonatal diseases - bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, perinatal hypoxic-ischemic encephalopathy and neonatal sepsis - and the available in vivo, in vitro and in silico preclinical models for studying these diseases. Better understanding of the strengths and weaknesses of specialized neonatal disease models will help to improve their utility, may add to the understanding of the mode of action and efficacy of a therapeutic, and/or may improve the understanding of the disease pathology to aid in identification of new therapeutic targets. Although the diseases covered in this article are diverse and require specific approaches, several high-level, overarching key lessons can be learned by evaluating the strengths, weaknesses and gaps in the available models. This Review is intended to help guide current and future researchers toward successful development of therapeutics in these areas of high unmet medical need.

Evaluation of Juvenile Animal Studies for Pediatric CNS-Targeted Compounds: A Regulatory Perspective.

Central nervous system (CNS)-targeted products are an important category of pediatric pharmaceuticals. In view of the significant postnatal maturation of the CNS, juvenile animal studies (JAS) are performed to support pediatric development of these new medicines. In this project, the design and results of juvenile toxicity studies from 15 drug compounds for the treatment of neurologic or psychiatric conditions were analyzed. Studies were conducted mostly in rats; sometimes in addition in dogs and monkeys. The study design of the pivotal JAS was variable, even for compounds with a similar therapeutic indication. Age of the juvenile animals was not consistently related to the starting age of the intended patient population. Of 15 compounds analyzed, 6 JAS detected more severe toxicities and 6 JAS evidenced novel CNS effects compared to their adult counterparts. The effects of CNS on acoustic startle and learning and memory were observed at high dosages. Reversibility was tested in most cases and revealed some small effects that were retained or only uncovered after termination of treatment. The interpretation of the relevance of these findings was often hampered by the lack of matching end points in the adult studies or inappropriate study designs. Detailed clinical observation and motor activity measures were the most powerful end points to detect juvenile CNS effects. The need for more detailed behavioral examinations in JAS, for example, on learning and memory, should, therefore, be decided upon on a case-by-case basis, based on specific concerns in order to avoid overloading the studies.

Use of paracetamol during pregnancy and child neurological development.

Paracetamol (acetaminophen) remains the first line for the treatment of pain and fever in pregnancy. Recently published epidemiological studies suggested a possible association between paracetamol exposure in utero and attention-deficit-hyperactivity disorder/hyperkinetic disorder (ADHD/HKD) or adverse development issues in children. However, the effects observed are in the weak to moderate range, and limitations in the studies' design prevent inference on a causal association with ADHD/HKD or child neurological development. In parallel, recent animal data showed that cognition and behaviour may be altered following exposure to therapeutic doses of paracetamol during early development. These effects may be mediated by interference of paracetamol with brain-derived neurotrophic factor, neurotransmitter systems (including serotonergic, dopaminergic, adrenergic, as well as the endogenous endocannabinoid systems), or cyclooxygenase-2. However, no firm conclusion can be made on the relevance of these observations to humans. We conclude that additional well-designed cohort studies are necessary to confirm or disprove the association. In the context of current knowledge, paracetamol is still to be considered safe in pregnancy and should remain the first-line treatment for pain and fever.