On Biostatistics and Clinical Trials: Pediatric Study Plan (PSP) and Paediatric Investigation Plan (PIP)

Pharmaceutical companies usually put their efforts into the adult population when they develop a new compound. There is usually low rates of pediatric testing that resulted in a paucity of information regarding the safe use of pharmaceutical products in children. While a common refrain heard from regulators is that "children are not simply little adults," physicians had little to inform with which to inform their prescribing habits. To encourage drug development in the pediatric population, the regulatory agencies have come up with different requirements and incentives. Pediatric Study Plan (PSP) and Paediatric Investigation Plan (PIP) are requirements in the US and EU respectively.

PSP in the US is the result of PREA (Pediatric Research Equity Act) and FDASIA (The Food and Drug Administration Safety and Innovation Act). Under FDASIA, signed into law on July 9, 2012, for the first time PREA includes a provision that requires manufacturers of drugs subject to PREA to submit a PSP early in the drug development process. The intent of the PSP is to identify needed pediatric studies early in drug development and begin planning for these studies. The timing and content of the submission of an initial PSP are described below. FDASIA requires the FDA to promulgate regulations and issue guidance to implement these and other provisions.

PIP (paediatric investigation plan) in EU is a development plan aimed at ensuring that the necessary data are obtained through studies in children, to support the authorisation of a medicine for children. All applications for marketing authorisation for new medicines have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver. This requirement also applies when a marketing-authorisation holder wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorised and covered by intellectual property rights.

Questions: Are PSP and PIP mandated or voluntary?

PSP and PIP are mandated unless it is waivered or deferred. Waiver means that the pediatric study/investigation plan is not needed. Deferral means that the pediatric study/investigation plan can be deferred to the post-marketing stage.

Question: How to obtain the waiver or deferral for PSP and PIP?

Under some circumstances, pediatric assessment may be unnecessary, undesirable, impractical, or delayed. In the US, the legislation authorizes FDA to grant waivers or deferrals to the pediatric assessments required under the Act. If the applicant requests a waiver or deferral, either full or partial, appropriate and sufficient supporting evidence must be provided. The criteria for granting waivers or deferrals center on safety, the nature of the drug product, and the practicability of the requisite studies. FDA has provided some specific information in a draft guidance, that describes how to comply with PREA.

In the EU, the Class waivers will be granted by the regulatory authority. "The need for a paediatric development may be waived for classes of medicines that are likely unsafe or ineffective in children, that lack benefit for paediatric patients or are for diseases and conditions that only affect the adult population. This page lists the class waivers granted by the European Medicines Agency (EMA)."

Question: what is the age cut point for defining the pediatric population

In the EU, pediatric population refers to children aged less than 18 years old.

In the US, pediatric population refers to children ages less than and equal to 16 years old. FDA further classify the pediatric population into the following categories:

NAME	DEFINITION	FDA CODE
NEONATES	NEWBORNS UP TO ONE MONTH	NEO
INFANTS	ONE MONTH TO TWO YEARS	INF
CHILDREN	TWO YEARS TO TWELVE YEARS	CHI
ADOLESCENTS	TWELVE YEARS TO SIXTEEN YEARS	ADO

An example of a partial waiver would be that PSP/PIP is not required for children less than or equal to two years old, but required for children greater than 2 years old.

Question: What are the incentives for doing pediatric studies?

In the US, As an incentive to industry to conduct studies requested by the Agency, Section 505(A) provides for a 6-month period of marketing exclusivity (pediatric exclusivity). in addition, FDA also has a Rare Pediatric Disease Priority Review Voucher Program that can issue a priority review voucher for companies who has drug development in rare pediatric disease. A priority review voucher can be worth millions of dollars.

In the EU, Rewards and incentives for paediatric medicines include the following:

· Medicines authorised across the EU with the results of studies from a paediatric investigation plan included in the product information is eligible for an extension of their supplementary protection certificate by six months. This is the case even when the studies' results are negative.

· For orphan medicines, the incentive is an additional two years of market exclusivity.

· Scientific advice and protocol assistance at the Agency are free of charge for questions relating to the development of paediatric medicines.

· Medicines developed specifically for children that are already authorised but are not protected by a patent or supplementary protection certificate are eligible for a paediatric-use marketing authorisation (PUMA). If a PUMA is granted, the product will benefit from 10 years of market protection as an incentive.

Question: Who will assess the PSP and PIP?

In the US, the PSP will be reviewed by the Pediatric Review Committee (PeRC).

In the EU, The Paediatric Committee (PDCO) is the committee at the European Medicines Agency that is responsible for assessing the content of paediatric investigation plan and adopting opinions on them. This includes assessing applications for full or partial waivers and assessing applications for deferrals.

References:

· US FDA (July 2013) Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans

· US FDA (July 2005) How to Comply with the Pediatric Research Equity Act

· US FDA Pediatric Product Development Webpage

· EMA Paediatric investigation plans

· EMA Paediatric investigation plans: Templates, forms and submission dates

· Current FDA Perspective & Future of JAS Testing to SupportPediatric Development Programs