Pediatric Drug Development: US and EU Regulatory Aspects

The number of drugs being labeled and tested for children has been growing during the past decade. This is largely due to legislation passed worldwide which regulates the area of pediatric drug development. Successful approaches in generating crucial information about pediatric drug safety and efficacy have been established both by FDA (the US Food and Drug Administration) and EMA (the European Medicines Agency).

These approaches improved accountability and transparency of drug development for pediatric patients, while pharma has to comply with more (and differing) regulatory requirements from these two organizations. Shaping these requirements are three key aspects:

  • Ethical
  • Operational
  • Scientific

With the patient population of children being more vulnerable, pediatric drug clinical studies differ from those in adults. Both planning and conduct of these studies need special attention and consideration of ethical and practical aspects, with particular regulatory guidance and attention being paid to the former one. The efforts in this area are addressing the following challenges:

  • finding of appropriate sampling strategies
  • defining of the first dose in children
  • generation of knowledge about efficacy, safety, pharmacodynamics, and pharmacokinetics in pediatric drugs
  • choice of the optimal methods for data collection and analysis
  • determining of the right dose and dosing regimen.

US regulatory aspects

The current growth in the demand of pediatric drug development is enhanced by the fact that many drugs have been administered to children without adequate understanding of their efficacy and appropriate dose and safety. The fact is that only a small percentage of all marketed drugs have proper labeling for pediatric patients and have undergone clinical trials in pediatric patients. Under the Pediatric Labeling Rule, a manufacturer can introduce changes to labeling upon submission to FDA of a supplemental new drug application (NDA).

The two US legislations for pediatric drug development are:

  • PREA (Pediatric Research Equity Act) which defines the requirements and covers both biologics and drugs, with the studies being mandatory (for indications under review only, excluding orphan indications)
  • BPCA (Best Pharmaceuticals for Children Act) which defines the incentives. With the studies being voluntary, it covers drugs only and allows to expand their indications (including orphan ones).

Both PREA and BPCA are designed to encourage more development and research of pediatric medicines. According to these acts, pediatric studies should be labeled, with the pediatric safety data being presented publicly to an advisory body one year after study conduct.

In 2007, the FDAAA introduced PeRC – the Pediatric Review Committee – consisting of FDA experts in chemistry, clinical pharmacology, pediatrics, statistics, legal issues, pediatric ethics, appropriate expertise, and a number of other designated experts. The function of this committee is to help ensure quality and consistency through providing framework and consultancy for the preparation to assessments and pediatric studies.

EU regulatory aspects

The objectives of EU regulation are:

  • to improve quality and ethical aspects of pediatric drug research
  • to increase available information on pediatric drugs without unnecessary studies in children and/or delaying authorization for adults
  • to increase availability of authorized pediatric drug.

To address these objectives, there are the following regulating instruments.

PDCO (Pediatric Committee) Being the counterpart of the US PeRC, this committee consists of experts in development and assessment of any aspect of medical products for pediatric use. The main responsibility of this body is content assessment of the submitted PIPs (Pediatric Investigation Plans) and issuing of opinions on their compliance with the EU pediatric regulation.

PIP – the basic document for development and authorization of a medical product for children – is to be submitted at an early phase of a new compound development (after Phase I, upon adult PK studies being available). The PIP explicitly defines timing of studies in children, which are conducted only when it is ethical and safe to do so, and can be deferred until the studies in adults are completed. After being amended and/or agreed upon by the PDCO, the PIP becomes a binding document for the company. The agreed-upon PIP can be further modified in the process of development, and in case of new information becoming available, through application to the PDCO.

To improve transparency and information availability, EMA established EudraCT (an EU database of clinical trials), which is an inventory of pediatric and medicinal product needs per therapeutic areas. Publicized in this database are all details and results of pediatric products’ clinical trials, including worldwide studies and those terminated permanently. EMA also provides free protocol assistance and scientific advice for rare or orphan diseases with regard to PIP development or PDCO decision.

Another organization, EnprEMA – European Pediatric Research Network – was established to forward high quality ethical research on medicine for children.

Differences in FDA and EMA regulations

Despite the identical goal to improve children’s health – to advance research and provide a reliable framework for safety and efficacy evaluation in pediatric populations and – FDA and EMA regulations show substantial differences.

  1. Pediatric development is mandatory in EU for all new drugs under development (unless they are granted a waiver), and the discussion for pediatric use of a product (submission of PIP) begins as early as adult PK studies are available.
  2. Unlike EMA’s PIP, FDA’s WR (Written Requests) is a voluntary document issued by FDA, while PIP is a mandatory one, proposed by the sponsor.
  3. PIP covers both incentives and non-clinical requirements, as well as complete product quality formulation (including age-appropriate one, deferral, and waiver requests), while WR covers incentives only, with requirements, waivers and deferrals being addressed by the pediatric plan (PREA).

In order to exclude the possibility of exposing children to unnecessary trials, and to decrease any risk for them during pediatric drug research, the FDA and EMA established a harmonized regulatory framework by implementing clinical research information exchange. However, this does not mean that pediatric product development programs may have exactly the same objectives or protocols or may be granted the same regulatory decisions.