Pediatric Requirements Pharmaceutical Companies Must Address

Part 3 of a 4-part series on Regulatory Frameworks, check out part 1 here about Regional Differences of Regulatory Frameworks for Pharmaceutical Approvals and Part 2 here comparing US, EU, UK and Global Health Authorities.

Ensuring the well-being of our youngest patients is a critical element in healthcare and is very challenging. Celegence works with companies in the global regulatory affairs space and has a unique perspective on the differences and similarities. We created this blog summary to compare the diverse pediatric requirements that pharmaceutical companies must address across the US, UK, EU, and Japan.

The main purpose of pediatric regulations is to ensure that medicines, developed for adults are also safe and efficacious for use with children. Pediatric plans, outline how drugs will be studied and used, and are crucial in ensuring medications are safe and effective for this younger population. These plans slightly differ across regions, shaped by diverse healthcare regulations and yet share some foundational similarities.

Two critical driving forces for Pediatric therapeutic development are:

• Safety and Efficacy: the primary objective is to ensure that drugs are safe and effective for use by children. Children often react differently to medications than adults.
• Age-appropriate Formulations: related to this is the objective to determine the correct dosage and dosage forms for various pediatric age groups, taking into account differences in metabolism, growth, and development as well as the ability to administer or to take the medicines.

All regions emphasize the importance of integrating pediatric needs early in the drug development timeline. Each region has a form of study plan though the requirements and implementation vary between them. These plans are crucial as they ensure the development of safe and effective medications for children from the early stages of drug development.

Juvenile pharmacokinetics and pharmacodynamics play a major role including studies to understand how drugs are absorbed, distributed, metabolized, and excreted in children, as well as their effects on the body.
Dosage Forms and Formulations – there are standards in developing age-appropriate formulations that are safe and acceptable for children, such as liquids, chewable, or dissolvable tablets, and ensuring that medications are palatable to improve consumption.

Ensuring that pediatric studies are conducted ethically, with parental consent and child agreement where appropriate.

In the US, the Food and Drug Administration (FDA), outlines the regulations and requirements. Pediatric studies are primarily governed by the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA). PREA mandates that drug companies study their products in children when the disease the drug treats also affects this population. The BPCA provides incentives for pharma companies to voluntarily conduct pediatric studies given high costs.

The FDA requires a pediatric study plan (PSP) before the start of pivotal trials and includes timelines for pediatric assessments. PREA allows for flexibility if studies are impractical or unsafe for pediatric populations. Overall, it insists on a methodical process to ensure that medications are adapted effectively for children.

In the US, there are several incentives to encourage the development of drugs for pediatric populations. Companies can receive market exclusivity extensions, tax credits, and grant funding to offset the additional costs and challenges associated with pediatric studies.  The Best Pharmaceuticals for Children Act (BPCA) offers an additional six months of market exclusivity if pharmaceutical companies voluntarily conduct pediatric studies as requested by the FDA, applying this extension to all existing patents and exclusivities on the drug.

The FDA provides significant regulatory assistance to support pediatric drug development. This includes scientific and regulatory guidance on designing and conducting pediatric studies, covering aspects such as study protocols, endpoints, and methodologies to ensure that the studies meet regulatory requirements. Drugs that address unmet medical needs in pediatric populations can qualify for priority review or fast-track designation, which can expedite the development and review process, helping bring essential pediatric treatments to market more swiftly.

Pediatric plans and development are overseen in the EU PDCO. The EU requires PIPs, Paediatric Investigation Plans (PIPs) for all new drugs being developed. The EU is particularly stringent about integrating pediatric needs early in the drug development timeline. The EMA also encourages shared development programs among companies to avoid unnecessary duplication of clinical trials in children, which speeds up the approval process and also reduces overall costs and burdens on pediatric populations. The PIP should be submitted as soon as human pharmacokinetic (PK) data becomes available, usually immediately following Phase 1.

The EU offers distinct incentives to encourage pediatric studies. For instance, a successful PIP can lead to an extension of market exclusivity. This extension is part of the incentives offered to encourage pediatric studies. According to European regulations, if a company conducts pediatric studies in compliance with an agreed PIP, the product can receive a six-month extension of its supplementary protection certificate (SPC) or a two-year extension of its data exclusivity. This incentive is granted regardless of the outcomes of the pediatric trials, meaning the extension is provided based on the completion of the trials as agreed in the PIP, not based on positive or successful results. This serves as a significant financial incentive for pharmaceutical companies.

The EU offers Pediatric Use Marketing Authorizations (PUMA) as a specialized regulatory pathway, granting market exclusivity for ten years regardless of the drug’s patent status. The US does not have a direct equivalent to PUMA but provides market exclusivity extensions through the BPCA. These extensions and incentives provide a similar benefit despite the differing structure. It is important to be aware of the subtle differences.

In the UK, pediatric plans and regulations follow closely to the EU and are governed by the Medicines and Healthcare products Regulatory Agency (MHRA).

The UK also mandates the development of PIPS. These plans are required for the approval of any new medicine, ensuring that potential pediatric use is considered from the early stages of drug development. The MHRA evaluates these plans to ensure a comprehensive assessment of benefits and risks for children. PIPs must include details on the timing of studies, the age ranges for child participants, and the formulations specific to pediatric use. Incentives are also available in the UK to offset development costs providing market exclusivity of up to 10 years.

Japan has specific guidelines under the Pharmaceuticals and Medical Devices Agency (PMDA), regulated by the Ministry of Health, Labour and Welfare (MHLW).

PMDA requires pediatric plans similar to those in the US. There is variation across Asia which means that companies often need to tailor their pediatric plans by country, navigating different levels of regulatory demands and clinical trial requirements.

In a similar way to the other regions, the purpose is to ensure that medicines developed for use in Japan are safe, effective, and appropriately dosed for pediatric populations. The guidelines outline the necessary steps for developing drugs for children, including clinical trial design, ethical considerations, and specific requirements for pediatric studies.

Japan allows for deferrals and waivers of certain pediatric studies. Studies can be delayed until after initial efficacy is demonstrated in adults. Studies may be waived if they are not feasible or necessary for certain age groups or conditions.

Pediatric study plans should be submitted early in the drug development process, ideally during the initial stages of clinical development. Early discussions with the PMDA are encouraged to ensure that the study design meets regulatory expectations.

The PMDA reviews pediatric study plans and provides feedback to ensure that the proposed studies will adequately assess the safety, efficacy, and appropriate dosing in children.

Both the US and EU regions provide opportunities for companies to seek scientific advice from their respective regulatory authorities. The EMA in Europe offers free scientific advice for questions relating to the development of pediatric medicines, while the FDA in the US provides guidance through its Pediatric Study Plan (PSP) process.

The EMA health authority advises that applicants can request pre-submission advice from EMA in preparation for a PIP. In addition, an applicant can seek Scientific Advice from PDCO, which is free of charge for questions relating to the development of pediatric medicines. They can also seek CHMP scientific advice, for example on combined adult and pediatric development. However, the EMA discourages applicants from submitting scientific advice and PIP applications in parallel.

Similarly, the UK’s MHRA offers scientific advice and regulatory guidance to support the development of pediatric medicines, helping companies navigate the regulatory requirements effectively.

In Japan, the PMDA also provides scientific advice to assist pharmaceutical companies in the design and conduct of pediatric studies, ensuring that they meet the necessary standards for approval.

Learn more about scientific advice regional differences here.

While the requirements are specific, there is flexibility built in to allow for different situations.  For example, most regions allow for flexibility if studies are impractical or unsafe for pediatric populations or if drugs are not expected to be efficacious in children, emphasizing a methodical process to ensure that medications are adapted effectively for children. The EU encourages shared development programs among companies to avoid unnecessary duplication of clinical trials in children, which not only speeds up the approval process but also reduces overall costs and burdens on pediatric populations. While these are not contrasting differences, they do show different points of emphasis to consider in the process.

Summarizing the various aspects of the programs, we see commonalities on attributes with some subtle differences in specs:

Understanding the regional differences in Pediatric drug development is crucial for pharmaceutical companies aiming to launch new drugs internationally. As regulations evolve and more countries recognize the importance of pediatric studies, the global field of pediatric drug development will likely continue to change, leading to better, safer medications and greater access for children worldwide.

While the core aim of pediatric plans—safer use of drugs for children—remains universal, the methods by which this is achieved reflect a diverse range of regulatory philosophies and practices. This diversity not only challenges international pharmaceutical companies but also opens opportunities for harmonization and improvement in pediatric healthcare.

Celegence has worked with Health Authorities around the world and helped pharma companies navigate the varying regulations by region.  In a recent survey that Celegence conducted together with RAPS (Regulatory Affairs Professional Society), ‘Navigating the changing regulatory landscape and keeping up with regulations’ was the #1 skillset that companies wanted to gain or acquire over the next 2-3 years. Get access to the full survey now.

Connect with us to discuss your needs for Pediatric Plans or assistance on Global Regulatory requirements.