Emerging patterns in the development of medicines in paediatric oncology

Abstract

Understanding how paediatric oncology medicinal products are developed may facilitate the approval of safe and effective medicines to treat children with cancer. The aim of this project was to review clinical development programs (CDPs) of medicinal products for acute lymphoblastic leukaemia (ALL) to identify emerging patterns in the development of medicines in paediatric oncology. CDPs for medicinal products approved in Europe through the centralised procedure to treat ALL in children were retrieved from European public assessment reports (EPARs) of the European Medicines Agency (EMA). CDPs for drugs in the development phase were retrieved from the EMA Paediatric Investigation Plans and from clinical trials registered in the EU clinical trial register and the United States national library of medicine database of clinical trials. Prospective treatment protocols for paediatric ALL were proposed to understand the potential impact that drugs in the development phase could have on clinical practice. The drug category and line of therapy was described for each authorised and prospective product. CDPs were analysed and compared based on the number, type and design of studies, and the endpoints used. Nine products (7 small molecules and 2 biologicals) were granted marketing authorisations under the centralised procedure to treat paediatric ALL. Three out of the 9 products authorised were new active substances and 6 were based on known active substances. Known active substances included PEGylated asparaginase and intravenous busulfan (new formulation) and oral liquids of methotrexate and mercaptopurine (paediatric friendly dosage forms). The 9 authorised products used 4 different types of marketing authorisation applications: (i) full applications (3 products), (ii) well-established use applications (2 products), (iii) hybrid medicinal product applications (2 products) and (iv) marketing authorisations under exceptional circumstance (2 products). The CDPs supporting the authorisation of products varied from extensive (10 adult trials, 2 paediatric studies and 1 pharmacokinetic modelling study) for products applying for first line indications through full applications to minimal (1 adult and 1 paediatric trial) for products seeking third line indications under exceptional circumstances. Thirty-five prospective products are in phase II and phase III development: small molecules (17 products including 2 novel liposomal formulations), advanced therapy medicinal products (9 ATMPs), biologicals (7 products including 2 novel PEGylated or erythrocyte-encapsulated formulations) and antibody drug conjugates (2 products). Drugs in the development phase will not significantly alter first line ALL treatment protocols in children. Prospective products for de novo ALL will likely be used as add-on therapies to the chemotherapeutic backbone established in past large scale trials. Monotherapy with biologicals, antibody drug conjugates or chimeric antigen receptor T-cell based ATMPs is being explored as a strategy to improve cure rates in relapsed or refractory paediatric ALL. Based on emerging patterns observed, this study suggests that companies are using 2 strategies to bring products for paediatric ALL to market: (i) Companies develop new formulations of the established products, such as liposomal, PEGylated or paediatric friendly dosage forms, as a drug development strategy to overcome acute toxicities, improve patient safety and promote treatment compliance, (ii) Companies that develop new active substances target niche (narrow) indications where there is an unmet medical need and may later extend indications through post-authorisation procedures supported by clinical trials in appropriately selected patient cohorts.