Optimizing Clinical Research for Pediatric and Underserved Populations
Solange Corriol-Rohou
AstraZeneca R&D, France
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nforcement of pediatric-specific regulations in both the United States and Europe since 2002 and 2007, respectively, has had a positive impact on pediatric drug development, with more medicines becoming available for children and more information on pediatric use becoming available to clinicians in the product information.

While great advancements in labeling for pediatric populations have been made since various regulatory frameworks were implemented in the US and Europe, important gaps still remain in underserved populations which are currently the focus of exciting and valuable initiatives as addressed in this paper.

The Regulatory Framework for Pediatric Drug Development

With the implementation of the RACE for Children Act in August 2020, the FDA is now authorized to require PREA pediatric studies when a molecular target of an adult cancer drug is relevant to a children’s cancer and has ended the orphan exemption for PREA studies.

In Canada, a 6-month data protection extension is granted to companies providing evidence to support a pediatric indication. In Japan, while there is also no pediatric legislation, there are however some incentives, such as priority for scientific advice by the Japanese Pharmaceuticals and Medical Devices Agency. In Switzerland, in addition to a 6-month pediatric supplementary protection certificate extension, a pediatric-specific law enforced in 2019 requires sponsors submitting a marketing authorization application to have an agreed pediatric plan; EU Paediatric Investigation Plans (PIP) or US initial Pediatric Study Plans (iPSP) are accepted for such purpose.

In Europe, while the implementation of the Orphan and of the Pediatric regulation have delivered benefits, both are currently being revised by the European Commission (EC) together with the general pharmaceutical legislation, with final revisions expected within the next five years. EC’s main goals are to foster the development of medicines for pediatric diseases in areas of unmet need; to ensure revised legislation is fit to embrace technological and scientific advances as well as timely access of patients to medicines, and to provide efficient procedures for clinical trials and medicines assessment and authorization.

Pediatric Drug Development and Global Alignment

Global regulatory alignment has been improved as a result of the COVID-19 pandemic, as we can see from the intense collaboration between regulators through the International Coalition of Medicines Regulatory Authorities (ICMRA). Sponsors can use a number of recommendations and procedures to facilitate pediatric drug development, such as the ICH E11(R1), ICH S11, or ICH E11A pediatric extrapolation guidelines; the EMA-FDA parallel scientific advice or common commentary on issues concerning pediatric oncology development; or the simultaneous submission of PIP and iPSP for oncology products to both EMA and FDA. The EMA-FDA common commentary released in 2020, although focusing on COVID-19 medicines, could easily be used for other conditions by providing a brief description of the information for inclusion in each section of the iPSP and the PIP.

Impact of Implementing the Pediatric Regulatory Framework

In October 2022, the FDA announced that they completed 1,000 pediatric labeling changes, a milestone for the agency’s public health mission. Historically, more than 80 percent of approved drugs were often used off-label in children.

Similarly, in Europe, as per the EC’s report of 10 years of pediatric regulation, over 260 new medicines were authorized for use in children between 2007 and 2016. The 2000 Orphan Regulation is considered a success, as the number of orphan designations (more than 2200) and of drugs registered for rare diseases (more than 160) has increased.

Gaps in Underserved Populations

During the EFGCP Pediatric Conference in 2022 and the Certara Symposium on New Horizons in Pediatric Drug Development in 2021, it was acknowledged that underserved populations that would benefit from R&D initiatives still exist. These are those suffering from rare diseases, neonates [term, post-term, and preterm newborn infants, as defined in the ICH E11(R1) guideline], and pregnant and breastfeeding individuals:

  • Rare diseases are generally severe, progressive, degenerative, life-threatening, or chronically debilitating, with a low prevalence. Most have their onset in childhood, and 80 percent are of genetic origin. While a large percentage undergoing active research are cancers, drugs for rare diseases encompass all therapeutic areas. Despite progress made, around 300 million children and adults suffer from a rare disease worldwide, which represents a huge unmet need and a significant public health challenge.
  • According to an FDA review, it was estimated that 65 percent of drugs given to neonates—and up to 90 percent used in neonatal intensive care units—are administered off-label. Neonatal information in labeling is even scarcer because neonates are a vulnerable subpopulation for which endpoint development and studies are challenging.
  • Pregnant and breastfeeding individuals are routinely excluded from clinical trials, and the resulting lack of data on product use and benefit-risk uncertainty is usually reflected through cautionary text in the product information. Uncertainties include the impact of medicine on the fetus or the child, as well as potential dosage implications resulting from physiological changes in pregnancy, which may impact the pharmacokinetics of medicines and ultimately lead to suboptimal efficacy and/or greater toxicity.

How to Address These Gaps?

Developing drugs for these populations involves complexities and challenges beyond those seen in common conditions. However, we do believe it is the right time to engage and coordinate collaborative actions to significantly impact patients’ lives. Activities are growing as shown by some initiatives.

It will be important to leverage the work done in both Europe and the US through public-private partnerships and to use better existing tools and methods to optimize drug development (e.g., quantitative approaches, complex innovative trial designs for small populations, real-world data as historical control) while developing others (e.g., new endpoints).

There will also be value in connecting with existing initiatives, collaborating with all stakeholders, including patients, to share learnings and optimize education and training of all involved. Similarly, using digital health technologies, whether to generate data or perform (fully or hybrid) decentralized trials, will change the way trials are done since these technologies are known to improve participant access to trials, retention, and diversity.

Here are some initiatives showing the interest is growing:

  • In 2020, the FDA funded a pivotal neonatal project, the INC/Critical Path Institute project supporting the use of RWD to generate RWE in neonates;
  • In 2022, the FDA released a guidance on General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products;
  • In 2022, the FDA organized a workshop on PK evaluation in pregnancy, and the ICH Assembly endorsed a new topic for a future guideline on the inclusion of pregnant and breastfeeding individuals in clinical trials; and
  • EURORDIS and EFPIA, which share the goal of ensuring broader and faster access to orphan medical products to all European patients, have recently decided to join forces to launch a Moonshot for rare and pediatric diseases and propose impactful solutions. It is expected that more coordinated, targeted, and collaborative basic and translational research will unlock a new wave of innovation.

A thoughtful dialogue with patients, disease experts, and regulators is pivotal in judiciously advancing all these approaches, including new ones.

To Conclude

Devising more efficient, less costly, and more patient-centric strategies to answer questions about treatment effects and patient benefits is key to shifting to personalized medicine for patients with unmet needs. This could involve developing and qualifying new biomarkers, designing complex innovative trials, and improving existing tools and methods and regulatory processes to optimize drug development and patient access to innovative medicines. To be more successful, early interactions with regulators as well as multistakeholder collaboration, patient involvement, shared learnings, training and education, and best practices are key.
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