Growing Requirements for Medicines for Children

Significant progress has been made in developing medicines for children since implementation of pediatric legislation in the US (1997) and EU (2006). However, gaps still exist, and regulatory authorities continue to address them.

In August 2017, the US passed the FDA Reauthorization Act and with it the Research to Accelerate Cures and Equity for Children Act (RACE). RACE for Children Act will eliminate exemptions and improve opportunities for cancer drugs to be developed for children by:

Requiring companies developing cancer drugs to do PREA studies in children when the molecular target of their drug is relevant to children's cancer

Ending the exemption of PREA obligations for cancer drugs with orphan designations if the molecular target of the drug is relevant to children's cancer 

In August 2018, the FDA will publish a list of molecular targets substantially relevant to growth and progression of pediatric cancer. It will also list molecular targets of new cancer drugs and biological products for which pediatric studies will be automatically waived.

Other positive steps include the following.

Congress reauthorized through 2020 the Rare Pediatric Disease Priority Review Voucher program in the 21st Century Cures legislation.

In the EU, the Commission report on 10 years EU Pediatric Regulation (October 26, 2017) showed encouraging impact of Pediatric Regulation overall, though the Regulation appears most effective when adult and pediatric needs overlap. Fewer advances have been made in diseases that are rare or unique to children. While some instances of over- or under-compensating drug developers with financial rewards exist, overall benefits seem to outweigh costs, and the Regulation appears to be improving pediatric medicine availability.

As a result, the European Commission does not recommend re-opening the legislation at this stage. It will evaluate pediatric and orphan Regulations to better understand their combined effects and why orphan rewards do not seem to be driving pediatric development for rare diseases. Findings are expected to be delivered in 2019, enabling the next Commission to make informed decisions about policy options.

In the meantime, the European Commission and EMA have begun working on measures to streamline application and implementation of the Regulation. This will include changes to deferrals, revisiting the PIP process, and, if needed, adapting corresponding Commission guidelines, multi-stakeholder discussion of pediatric needs, measures to encourage international cooperation, and harmonization.

In respect to deferrals, a revised and revoked class waivers list will come into effect in July 2018 (8 waivers were revoked, 15 updated, and 9 confirmed). From July 2018 on, applications for new medicines or variations of marketing authorization will be validated against this list. Waivers, specifically those in oncology, will no longer be automatic. Regulators will expect companies to have considered product mechanism of action and pediatric needs prior to deciding on them.

Regarding multi-stakeholder discussion of pediatric needs, the EU Commission and EMA held a workshop with patients, academia, healthcare professionals, and industry on March 20, 2018. Potential improvements to implementation of the Regulation (pediatric needs, timely completion of PIPs, processes, expectations for handling them) were discussed. An action plan addressing challenges will be published mid 2018. The EMA, EU Commission, and stakeholders will need to commit to execution of it within two years.

ICH E11 (R1) "Clinical Investigation of Medicinal Products in the Pediatric Population" entered into force in February 2018 and aims to further improve pediatric research globally. Addendum R1 reflects latest thinking in technical, scientific, and regulatory approaches and recognizes key topics where consensus had not been achieved, including:

Ethical considerations

Age classification and pediatric subgroups including neonates

Pediatric formulations

Common scientific approaches to aid discussions in different regions 

Pediatric extrapolation and introduction of modeling and simulation

Practicalities in design and execution of pediatric trials, including feasibility, outcome assessments, and long-term clinical aspects.

Global progress is ongoing.  ICH E11 A "Pediatric Extrapolation Guideline" was discussed at the ICH meeting in Geneva (November 2017) and is expected to reach Step 2a by November 2020. ICH S11 "Safety Testing in Support of Development of Pediatric Medicines" is expected to reach final stage, Step 4, in June 2019.

These are promising steps toward making better medicines available to treat children.

Dr. Martine Dehlinger-Kremer has 30 years of experience in the clinical research industry. She has contributed to global development of numerous products, including orphan drugs and biosimilars. She has participated in 100+ New Drug Applications and Marketing Authorization Applications globally and in clinical studies across all phases.

Dr. Dehlinger-Kremer has served as Chair of the Pediatric Working Group of EUCROF since 2008 and Chair of the European Forum for GCP (EFGCP) Children Medicines Working Party. She is a member of Working Parties of Enpr-EMA, the European Network of Pediatric Research at the European Medicines Agency. She was recently appointed as observing Member of the Coordinating Group of Enpr-EMA. She is also President of EUCROF, the European CRO Federation, representing 350+ CROs, and a Board Member of EFGCP.

Dr. Dehlinger-Kremer holds a Doctorate in Sciences, Master of Advanced Study in Neurophysiology degree, and a Master of Science degree.

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