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Regulatory Challenges in Pediatric Drug Development: The European Perspective

It is important for anyone developing therapeutics that could be used to treat pediatric populations to take into account both FDA and EU regulations. EU Regulations seek to improve children’s health by: increasing high-quality, ethical research of medicines for children; increasing the availability of authorized medicines for children; and increasing information about medicines without conducting unnecessary studies on children or delaying medicines’ authorization for adult populations.

When are Pediatric Investigation Plans (PIPs) Required?

Pediatric development is mandatory in the EU for new products unless a waiver is granted. Waivers can be either product-specific or class-specific and only apply to specific conditions and dosage forms. Deferrals can be granted that allow studies in children to be completed after applying for marketing authorization in adults. For existing products, a Pediatric Investigation Plan (PIP) is mandatory when seeking a new indication, route, or dosage form if the product is protected by a patent or a Supplementary Protection Certificate (SPC). Off-patent products already authorized in the EU that do not have a valid SPC do not require PIPs. They are also not required for new medicinal products in certain groups, including traditional herbal products, homeopathic products, generic products, hybrid products, and biosimilar products. There are three types of waivers:

  • Total waivers apply to all pediatric subsets of specific conditions.
  • Partial waivers apply to some pediatric subsets or some indications but still require a PIP.
  • Some classes of products for a condition or all products for a condition may have a class-waiver.

The legal grounds for obtaining a waiver are (1) a product is not safe or effective in pediatric populations, (2) the disease or condition occurs only in adult populations, or (3) there is no significant therapeutic benefit in pediatric populations. The EMA may grant a deferral to avoid delaying marketing authorization in adults and may allow one or more studies in the PIP to be completed after the marketing authorization application (MAA). Deferrals are granted at the study or measure level. In some cases, regulators may require that sponsors initiate pediatric trials prior to marketing authorization, but may grant marketing authorization for adult populations prior to the completion of the pediatric trials. All types of deferrals must establish completion dates. Incentives are available for all correctly completed PIPs, and additional incentives are available for voluntary development through the Pediatric-Use Marketing Authorization (PUMA) program. “Correctly completed” means that the studies performed comply with the PIP agreed to in the compliance statement of the marketing authorization (MA), the results of studies are in the Summary of Product Characteristics (SmPC) and the patient’s leaflet, and the product is authorized in all member states (except for PUMA candidates). Non-orphan products can receive a 6-month extension on patent protection. Orphan products can receive two additional years of market exclusivity. Products submitted under PUMA can receive eight years of data protection, two additional years of market protection, and a partial EMA fee exemption for a year. Incentives are provided even when the PIP results are negative, but not when the results are inconclusive or when a waiver is granted.

What Does a PIP Cover?

PIPs are designed to collect data on efficacy, safety, and age-appropriate formulation. The PIP will outline studies needed and may include nonclinical studies in juvenile animals (i.e., toxicology, pharmacodynamics, pharmacokinetics, carcinogenicity, genotoxicity), safety, and proof-of-concept studies, dose-finding studies, and efficacy studies. PIPs will also provide timelines for each study. For new products, PIPs should be developed by the end of phase 1 clinical trials in adults. Amendments to the PIP may be made throughout phase 2 and phase 3. Data from adult studies cannot provide a full picture of the safety of a product in a pediatric population. Animal studies and clinical trials in pediatric populations are needed to determine the impact of a therapeutic on organ development, growth, maturation of function, neurobehavioral development, and realization of potentials. It is essential to ensure that pharmacovigilance mechanisms are adapted to meet the specific challenges of collecting safety data in a pediatric population, including data on possible long-term effects. Sponsors may be required to set up a risk management system or conduct specific post-marketing studies in instances where there is a particular cause for concern. Sponsors should start thinking about pediatric development early. Getting an agreement on a PIP with EMA typically takes 8-12 months and needs to be done before studies in children begin. 

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