Correspondence

Will the revised class waiver list make it?

There are profound anatomical, physiological, and developmental differences between immature and mature systems leading to differences in the metabolism, renal clearance, drug-drug interactions, and overall response to medications. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulations have significantly changed the pediatric drug development process. Pharmaceutical companies are now encouraged to start considering their pediatric assessments and appropriate study plan early in development. The increased interest and/or need to perform pediatric clinical trials for marketing and safe use of a wider range of drugs in children have raised the necessity for juvenile animal studies. Guidance documents have been issued for the nonclinical safety testing of juvenile animals in the United States, Europe, and Japan. The juvenile toxicity study design is approached case by case based on scientific rationale and should mimic the pediatric clinical trial. Critical points relevant to juvenile animal studies include the need to design studies focused on addressing specific questions pertinent to children, rather than adapting standard toxicology designs to juvenile studies. Activities aimed at harmonizing these guidelines and conforming to the current state of science have been completed. ICH S11 on nonclinical safety studies to support a pediatric development program was endorsed by the members of the ICH Assembly on September 18, 2018 and adopted by the Regulatory Members of the ICH Assembly on April 14, 2020. This chapter covers regulatory aspects of pediatric development, nonclinical safety guidelines, weight of evidence (WoE) approach, study design considerations, technical and logistical limitations of conducting neonatal/juvenile toxicity studies as well as the use of juvenile animal data in risk assessments.

New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic–pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.

United States (US) Pediatric Legislation (PL) was introduced in 1997 to improve children‘s health. The European Union PL (EUPL) has been in force since 2007. Both PLs facilitate additional pediatric research on primarily adult drugs. The EUPL declares that the forces of the market are not sufficient for children. Without a pediatric investigation plan, new drugs can no longer be registered with the European Union. New ways on how to facilitate drug development for rare pediatric diseases are being proposed.

US PL, EUPL, and implications of modern labels for medical decision making are discussed.

Modern drug labels constituted a step from eminence-based towards data-based medical decision making. However, approval by regulatory authorities did not replace knowledge transfer in medicine, which continued in university education, through conferences, consensus papers, and so on. Children were successfully treated with off-label drugs in pediatric oncology and in many other diseases. Describing children as “therapeutic orphans” reflected an overestimation of drug labels and an underestimation of nonregulatory systematic clinical testing. Therapeutic breakthroughs have occurred, for example, in acute myelogenous leukemia and cystic fibrosis. Rare diseases need new innovative drugs and therapeutic concepts for further breakthroughs.

The focus of PL on additional pediatric measures for predominantly adult new drugs reflects a tunnel view. Similar to the introduction of modern pharmaceutical legislation that triggered comparable laws in most countries worldwide after 1962, we currently need new worldwide steps to reward innovative treatment concepts for rare diseases—not against, but through the market. Created by philanthropy, parents, and other supporters, new therapeutic concepts should be rewarded upon meeting regulatory milestones. This market is limited today. It needs not only a boost by pioneers, but also acceptance, welcome, and re-thinking about drug development in academia, politics, and by the general public.

There are profound anatomical, physiological, and developmental differences between immature and mature systems leading to differences in the metabolism, renal clearance, drug–drug interactions, and overall response to medications. US FDA and European (EMA) regulations have significantly changed the pediatric drug development process. Pharmaceutical companies are now encouraged to start considering their pediatric assessments and appropriate study plan early in development. The increased interest and/or need to perform pediatric clinical trials for marketing and safe use of a wider range of drugs in children have raised the necessity for juvenile animal studies. Guidance documents have been issued for the nonclinical safety testing of juvenile animals in the United States, Europe, and Japan. The juvenile toxicity study design is approached case-by-case based on scientific rationale and should mimic the pediatric clinical trial. Critical points relevant to juvenile animal studies include the need to design studies focused on addressing specific questions pertinent to children, rather than adapting standard toxicology designs to juvenile studies. Activities aimed at harmonizing these guidelines and conforming to the current state of science have already started. ICH S11 on nonclinical safety studies to support a pediatric development program is expected to be completed in 2016 and implemented in 2018. This chapters covers regulatory aspects of pediatric development, nonclinical safety guidelines, study design considerations, technical and logistical limitations of conducting neonatal/juvenile toxicity studies as well as the use of juvenile animal data in risk assessments.

Alors que la médecine de précision et l’immunothérapie donnent déjà des premiers résultats très prometteurs dans les cancers des adultes, et que près de 1000 molécules sont en développement par l’industrie pharmaceutique, il est primordial de ne pas oublier les enfants et les adolescents pour lesquels le cancer reste la première cause de décès par maladie. Si le Règlement européen a changé le paysage du développement des médicaments en pédiatrie, il n’a pas encore eu les effets attendus dans les cancers pédiatriques. L’opportunité de pouvoir modifier ce règlement et son implémentation en 2017 mobilise aujourd’hui les différents acteurs (chercheurs et pédiatres, parents, industriels, réglementaires) qui, ensemble, au sein d’une plateforme européenne Accelerate et par une alliance des associations de parents Unite2Cure, ont analysé les obstacles et limites de la réglementation afin d’élaborer et formaliser des propositions de changement : supprimer les exemptions de développement qui sont scientifiquement et médicalement injustifiées ; mettre en place un système de priorisation pour choisir les molécules potentiellement les plus efficaces ; réduire les retards à l’initiation des développements pédiatriques ; casser le dogme de la barrière des 18 ans ; installer un système efficace et adapté de récompenses et de sanctions. Plusieurs actions majeures sont ainsi menées en France et en Europe pour mobiliser les parlementaires et les états-membres afin d’accélérer le développement de traitements plus efficaces et innovants en oncologie hématologie pédiatrique. L’objectif est d’obtenir l’amélioration du règlement pédiatrique et de favoriser l’investissement des industriels dans la recherche et le développement d’innovations thérapeutiques pour les enfants et les adolescents atteints de cancer. Il est important d’agir maintenant pour se donner les moyens de les guérir plus et mieux.

Precision cancer medicine and immunotherapy are delivering very promising results for the treatment of adult cancers and more than 1000 new oncology compounds are currently developed par the Pharmaceutical industry. It is crucial that children and adolescents are not left apart since cancer remains the leading cause of death by disease beyond 1 year of age. The European Pediatric Medicine Regulation that was launched in 2007 clearly changed the landscape for evaluation of medicines in children, but it is far for having addressed yet adequately the urgent therapeutic needs in pediatric oncology. In 2017, there is an opportunity to change the regulation and its implementation. All stakeholders (pediatric oncologists, researchers, parents, regulators, industry) joined forces through the Accelerate platform and the Unite2Cure parents organization alliance to analyze, together, the limitations of the current regulation and to propose solutions: suppress waivers that are both scientifically and medically unjustified; set up an efficient prioritization system to choose the potentially best new oncology drugs to develop in children; break the 18 years dogma; install an efficient and adapted system of rewards and sanctions. Several initiatives are currently being developed in France and in Europe to mobilize members of the Parliament and Member-states in order to improve the regulatory environment and to better incentivize industrial investment in research and development of innovations for children and adolescents with cancer. It is crucial to act now in order to cure them more and better.