The RACE to accelerate drug development for children with cancer
Cancer remains responsible for the deaths of many children and adolescents. Improvements in survival rates for childhood malignancies have plateaued despite the extensive implementation of clinical trials and multidisciplinary approaches to treat these cancers. More than 20% of children with cancer still die from the disease and 40% of survivors live with long-term disabling sequelae into adulthood. Novel drugs targeting oncogenic drivers or the immune microenvironment, or with other mechanisms of action, are therefore needed in paediatric oncology, like the approaches used for some adult cancers, which have resulted in good outcomes. Through a greater understanding of the biology of childhood malignancies, novel agents with specific mechanisms of action are being identified. For example, selective tropomyosin receptor kinase inhibitors, B-Raf inhibitors, and anaplastic lymphoma kinase inhibitors for tumours with relevant translocations or mutations, and immune checkpoint inhibitors for tumours with high mutational burden, have resulted in a shift in paediatric cancer therapy.1
However, notably more anti-cancer medicines are registered in adults, and very few are approved for use in children, as the extension of scientific development to cancers in children has been both delayed and limited, partly because the substantial requirements and because the incentives for paediatric assessments of new cancer drugs have historically not been available. The 2006 European Paediatric Regulation requires an agreed paediatric investigation plan to be produced before marketing authorization is given for medicines being developed for adults, unless a waiver is granted by the Paediatric Committee at the European Medicine Agency.2 This regulation was a major advance in improving paediatric access to innovative medicines. However, it remains that the starting point for paediatric drug development is the adult condition. As a consequence, 54% of medicines that had regulatory requirements for paediatric assessment waived had mechanisms of action that were relevant to paediatric tumours.3 In addition, there have been substantial delays (median 6.5 years) in starting paediatric trials after the initiation of first-in-human trials.4
Challenges to accelerating drug development for childhood cancers and ultimately introducing innovative medicines into standard care include: suboptimal collaboration between stakeholders (patients, parents, and their advocates; paediatric haematologists and oncologists, pharmaceutical companies, and regulatory agencies), drug development centred on adult conditions, and delayed and diminished access to new drugs for paediatric investigations.
In 2015, ACCELERATE was created as an international multistakeholder platform, with the aim of accelerating innovation in drug development and using a science-driven approach to meet the needs of children and adolescents with cancer.5 This global endeavour brings together patient advocates, paediatric haematologists and oncologists, pharmaceutical companies, and regulatory agencies, across Europe, North America, and Australia to work as equal partners.
In 2016, ACCELERATE New Strategies for Development of Oncology Drugs Working and Group proposed a mechanism of action-based approach for paediatric oncology drug development, rather than being driven by the adult condition.6 In this approach there would be increased opportunities for evaluation of new drugs in children, which could otherwise be waived or paediatric studies might not be proposed. Another ACCELERATE initiative was the creation of Paediatric Strategy Forums to facilitate meaningful interaction between all stakeholders on topics from an industry or academic standpoint, and to prioritise studies of drugs with similar mechanisms of action in the setting of low patient numbers. Five Paediatric Strategy Forums have been held on anaplastic lymphoma kinase inhibition, mature B-cell malignancies7, immune-checkpoint inhibitors in combination, acute myeloid leukaemia and epigenetic modifiers8, with a sixth planned on chimeric antigen receptor T-cells. These Forums have been successful in evaluating pre-clinical and clinical research, increasing understanding, and facilitating decisions on the prioritisation of compounds in development for specific cancers or broadly across all cancers in children, and their value has been appreciated by regulators.8
Importantly, there is now an exciting and evolving regulatory environment for paediatric oncology drug development in the USA and Europe. While acknowledging the progress, sustained effort is required to realise the goal of timely development of treatments for children with cancer. The ongoing evaluation by the EU on both the paediatric and orphan regulations will potentially further enhance the regulatory environment in Europe. In addition, implementation of paediatric legislation in the USA is poised to provide substantial opportunities for drug development.
A landmark in accelerating the investigation of innovative drugs is the full implementation of the Research to Accelerate Cure and Equity (RACE) for Children Act and the Food and Drug Reauthorization Act amendments to section 505B of the Food, Drug, & Cosmetic Act in the USA in August, 2020, 9 which is complementary to the EU Paediatric Regulation. The RACE for Children Act requires that drugs and biological products be assessed early in paediatric cancers if the drug or biological product is directed at a molecular target determined to be substantially relevant to the growth or progression of a paediatric cancer.9 The Act will end drug exemptions from paediatric trials based on development for adult cancer histologies not seen in children, or exemptions based on orphan status of an adult indication. Although a USA-based regulation, The RACE for Children Act will alter the global landscape of the development of cancer drugs, which target pathways that drive certain adult cancers and also exist in paediatric cancers, and active beneficial drugs will require assessment in children in the early stages of the drug’s development. However, the Act does present challenges, as it is unlikely that trials of all the potential drugs of a certain class could be completed in view of the low numbers of available patients. Therefore, a consensus prioritisation will be essential and should involve academia, industry, and patient advocates. The Food and Drug Administration, in its draft guidance on implementation of the RACE for Children Act, encourages participation in multi-stakeholder meetings, such as Paediatric Strategy Forums, to achieve this objective.10
Enhanced global dialogue and understanding, as well as transparency between all stakeholders can result in a model of drug development based on mechanism of action. Together with supportive regulatory environments, children with cancer should have more opportunities to access safe and effective, innovative medicines more rapidly. This approach might also be applicable for other rare, life-threatening conditions in childhood.
ACCELERATE receives financial support from the Andrew McDonough B+ Foundation. ADJP reports personal fees from Novartis, Takeda, Merck, Celgene, and Lilly, outside the submitted work. SGD reports personal fees from Bayer, and travel expenses from Salarius and Roche, outside the submitted work. All other authors declare no competing interests. The views expressed in this Comment are the personal views of the authors and may not be understood or interpreted as being made on behalf of or reflecting the position of the regulatory agencies or organisations with which the authors are employed or affiliated.
*Andrew D J Pearson, Dominik Karres, Gregory Reaman, Steven G DuBois, Leona Knox, Nicole Scobie, Gilles Vassal
ACCELERATE, Europe (ADJP, GV); Paediatric Medicines Office, Scientific Evidence Generation Department, Human Medicines Division, European Medicines Agency, Amsterdam, Netherlands (DK); US Food and Drug Administration, Silver Spring, MD, USA (GR); Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA (SGD); Solving Kids’ Cancer, London, UK (LK); Zoé4life, Sullens, Switzerland (NS); Childhood Cancer International, Europe (NS); and Gustave Roussy Cancer Centre, Villejuif, France (GV)
1 DuBois SG, Corson LB, Stegmaier K, Janeway KA. Ushering in the next generation of precision trials for pediatric cancer. Science 2019; 363: 1175–81.
2 EU. Regulation (EC) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No. 1768/92, Directive No. 2001/20/EC, Directive No. 2001/83/EC and Regulation (EC) No. 726/2004. 2006. http://www.wipo.int/wipolex/en/details.jsp?id=5940 (accessed June 18, 2020).
3 Pearson ADJ, Pfister SM, Baruchel A, et al. From class waivers to precision medicine in paediatric oncology. Lancet Oncol 2017; 18: e394–404.
4 Neel DV, Shulman DS, DuBois SG. Timing of first-in-child trials of FDA-approved oncology drugs. Eur J Cancer 2019 ; 112: 49–56.
5 Vassal G, Rousseau R, Blanc P, et al. Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer. Eur J Cancer 2015; 51: 218–24.
6 Pearson AD, Herold R, Rousseau R, et al. Implementation of mechanism of action biology-driven early drug development for children with cancer. Eur J Cancer 2016 ; 62: 124–31.
7 Pearson ADJ, Scobie N, Norga K, et al. ACCELERATE and European Medicine Agency Paediatric Strategy Forum for medicinal product development for mature B-cell malignancies in children. Eur J Cancer 2019 ; 110: 74–85.
8 Karres D, Lesa G, Ligas F, et al. Can a multistakeholder prioritization structure support regulatory decision making? A review of Pediatric Oncology Strategy Forums reflecting on challenges and opportunities of this concept. Clin Pharmacol Ther 2020; published online June 19. https//:doi.org.10.1002/cpt.1939.
9 US Congress. FDA Reauthorization Act of 2017. 2017. https://www.congress.gov/115/plaws/publ52/PLAW-115publ52.pdf (accessed June 18, 2020).
10 US Food and Drug Administration. FDARA implementation guidance for pediatric studies of molecularly targeted oncology drugs: amendments to sec. 505B of the FD&C Act. Guidance for industry. 2019. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fdaraimplementation-guidance-pediatric-studies-molecularly-targetedoncology-drugs-amendments-sec (accessed June 18, 2020).
* ACCELERATE receives financial support from Andrew McDonough B+ Foundation