Paediatric Oncology: Update from 11th ACCELERATE Annual Conference

DLRC attended the ACCELERATE conference to obtain more insight on the current issues and developments within the field of paediatric oncology, which is an area of high unmet need, as cancer is still the leading cause of disease-related death in children. The conference consisted of 6 presentation-based and 3 breakout sessions. Highlights from the 2-day conference are outlined below:

Real-World Data in Paediatrics

During the first session, the activities to-date and next steps of the Childhood Cancer Data Initiative (CCDI) were presented along with useful data and tools released for public use as of yet (e.g., NCCR paediatric explorer, CIViC Data Platform, Childhood Cancer Data Catalog, Molecular Targets Platform).  From the European perspective, the framework of ITCC-data integration platform was presented which aims on real-world data capture, harmonisation of data dictionaries and omics pipeline, as well as data visualisation and sharing through the paediatric cancer data portal.

The SACHA project, which is a French observational non interventional study with an aim to expand to other countries under the SACHA INTERNATIONAL (ITCC-105), was introduced. The SACHA study is a real-world data program collecting prospective data on a national scale on safety and efficacy of innovative therapies administered to children with a recurrent/refractory malignancy outside of clinical trials prescribed off-label or on compassionate use.

Other initiatives discussed are the ACCELERATE logbook, a planned registry (currently in the preparatory phase) to collect the post marketing late adverse effects of recently approved targeted and immune therapy medicines. In addition, the DARWIN EU federated network was introduced, and examples were provided on how it will support regulatory decision-making and the evaluation work of EMA’s scientific committees and National Competent Authorities.

Perspective from Patient Advocates

In the second session, patient advocates highlighted the importance of participation of advocates in drug development and their input on the design of clinical studies for paediatric cancers. Some of the issues important for advocates were presented, including the role of Randomised Clinical Trials (RCTs) in drug development for relapsed/refractory poor prognosis children’s cancer, simultaneous development of companion diagnostic, ethical rationale for tissue sampling and cost of novel therapies. The necessity of intercontinental collaboration in paediatric oncology trials was also a key message. Although these obstacles are acknowledged (e.g. regulatory non-alignment, differences in standard of care, funding and resources), it was shown that intercontinental trials are feasible based on examples of successfully conducted studies.

The FAIR (Fostering Age-Inclusive Research) group also presented their efforts for making clinical studies inclusive for the AYA group, which amongst others included the introduction of the “FAIR stamp”. This recognition can be applied for by sponsors and is awarded to trials that are actively avoiding barriers based on the age of participants.

Last but not least, the access to paediatric medicines and great variability in decision and time between countries was highlighted based on an analysis of 3 drugs in 9 countries, along with proposed recommendations to improve access to newly approved medicines. The upcoming HTA regulation (which will be implemented in 2025) could alleviate some of the aspects of the inharmonious drug access landscape in Europe.

Regulatory Landscape Updates

An update to the regulatory landscape in Europe and North America were presented by regulators and other relevant stakeholders. It was recognised that the RACE for Children Act has resulted in substantive improvement in drug development within the field of paediatric oncology, with an increased number of paediatric investigations for new molecular entities directed at a relevant molecular target.

Also, during the breakout session it became obvious that companies (especially large pharma) became more proactive in incorporating paediatric planning in pre-clinical and early clinical phases, albeit there are still barriers to fully realise a high-quality mode-of-action based program in children (e.g. lack of established criteria for objective assessment of activity). From the European perspective, regulators understand that fostering a R&D environment that allows evolution of scientific knowledge, the changing evidence and unmet need is needed. In particular, collaboration amongst the various relevant stakeholders, i.e., patients/parents, industry, academia and regulators is needed to prioritise different pipelines based on science.

In addition, there was an emphasis on how a Paediatric Investigational Plan (PIP) should be considered a living document that will allow regulators to provide continuous support, and ensure the plans are still fit for purpose. In general, early phase studies should be considered as a starting point, trying to maximise data generation using novel methodologies (e.g. platform studies) to inform the development towards a final target population and pivotal study design considerations. Such go/no-go decisions should be incorporated early in development to inform whether further studies or expansion cohorts are warranted.  Pivotal development could then be included at a high level or in the form of “placeholder” studies, formulated based on the awaited supportive evidence.

Finally, a representative from European Commission provided a general overview of the upcoming changes in the EU Paediatric Regulation. In broad terms the Regulation could see the following changes:

• Formalising a “stepwise PIP” framework,
• Introduce the concept of mechanism of action for waivers (similar to USA),
• The possibility to review deferrals aiming to limit long unjustifiable deferrals
• Increased transparency for PIP discontinuations
• Formalise multistakeholder discussion on prioritisation.

Paediatric Patient-Reported Outcomes (PROs)

The use of patient-reported outcomes (PROs) in paediatric clinical trials was another topic that was covered in the conference and examples of some of the latest developments in PRO measures available for paediatric oncology trials were presented (e.g. PROMIS, PRO-CTCAE). In addition, an insight into ePROs and their gamification was presented and how these methods can facilitate the implementation of PROs in studies.

During the breakout sessions it was acknowledged that the use of PROs should be increased in paediatric clinical development, but further frameworks and tools are needed to support implementation of PROs meaningfully that would be beneficial for the regulators, the companies, and the patient.

Pre-clinical Prioritisation

Insights into the workings of groups on pre-clinical testing in the EU (EU-funded ITCC4-P4) and US (NCI-funded PIVOT) were shared. PIVOT offers an in vivo testing program able to test multiple classes of agents (and combinations) to help drug developers, researchers and regulators to make informed decisions about further clinical testing in children. In similar fashion, the ITCC-P4 aims amongst others to establish a representative collection of patient-derived in vitro and in vivo models, to molecularly characterise and quality-assess those models, help with the prioritisation of drug development, identify relevant biomarkers and offer a standardised preclinical testing that will expedite the development of more precise and efficacious drugs.

In conclusion, the ACCELERATE conference showcased the vast efforts across different disciplines and stakeholders to enhance and promote drug development in this field of high unmet need, where typical drug development paradigm cannot always be adopted.

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