PIP: paediatric investigation plan

The paediatric investigation plan is created by Regulation (EC) No 1901/2006, the Paediatric Regulation. Article 7 makes an agreed PIP, a waiver or a deferral a condition of validation for any application for a new medicine, and Article 8 extends the requirement to new indications, pharmaceutical forms and routes of administration for authorised products protected by a patent or supplementary protection certificate. The plan describes the studies, formulations and timelines needed to support use in each paediatric subset, and the Paediatric Committee of EMA assesses and agrees it.

Under Article 16 the plan must be submitted no later than completion of the adult human pharmacokinetic studies, early enough for the paediatric programme to be integrated into development. Waivers under Article 11 are available where the condition does not occur in children, the product is likely to be unsafe or ineffective in them, or it offers no significant benefit over existing treatments; class waivers published by EMA cover whole conditions. Deferrals under Article 20 allow the paediatric studies to be completed after the adult authorisation, which is the usual pattern. Modifications of an agreed plan are requested under Article 22 as development evolves.

At the time of the marketing authorisation application the applicant provides the results of the studies, or evidence of a waiver or deferral, and EMA or the national authority checks compliance under Article 23. Completion of the agreed plan earns the rewards in Articles 36 and 37: a six-month extension of the supplementary protection certificate, or two extra years of orphan market exclusivity. Results of completed paediatric studies must be submitted under Articles 45 and 46 even when not part of a plan.

What goes wrong: submitting the plan late, so the application cannot be validated until the Paediatric Committee has agreed it; proposing studies that cannot be delivered on the timeline, which later require modification requests; and a compliance check that fails because a study deviated from the agreed measures without a modification. Formulation work is often underestimated, and an age-appropriate formulation is a frequent binding element of the plan that the compliance check will look for.