Mediplex has a special interest in writing paediatric investigation plans (PIPs) and waiver/deferral requests, and is supported by other consultants and academics with expertise in the following:

• Paediatric formulation development
• Juvenile animal studies
• Pharmacokinetic modelling
• Paediatric pharmacokinetics and clinical trials

The PIP is a key element in the new EU Paediatric Regulation, which came into force on 26 January 2007. It includes obligatory requirements. The PIP is a plan for defining the use of a medicinal product across all age groups of the paediatric population (namely preterm neonates, term neonates, infants and toddlers, children (aged 2-11 years) and adolescents), and across all indications. The Paediatric Commitee (PDCO) is the new body within the European Medicines Agency (EMEA) responsible for overseeing the requirements of the Paediatric Regulation. The PDCO may grant a waiver from using a medicinal product in certain (or all) indications and/or certain (or all) paediatric age groups, and/or a deferral of the start or completion of all or some of the studies in the PIP. The PDCO has granted class waivers for some classes of drugs that are used to treat conditions only occurring in adults, e.g. Alzheimer's disease. In all other cases, waivers must be applied for on a product-specific basis.

A summary of the Paediatric Regulation, together with various commentaries on it, can be found in an article by Dr Hession published in Regulatory Rapporteur March 2007; 4(3): 26-28.

Submitting a PIP and/or a waiver request is only obligatory for medicinal products previously unauthorised in the EU and for patent-protected products (those covered by a patent or Supplementary Protection Certificate [SPC]) being developed for use in new indications, routes of administration or pharmaceutical forms. In these cases, a PIP and/or a waiver request must be submitted for assessment by the PDCO no later than at the end of human pharmacokinetic studies in adults (taken to mean after Phase I and/or before Phase II), unless otherwise justified. Generic and biosimilar products are exempt from these obligatory requirements, as are bibliographical applications and herbal and homeopathic products.

Companies wishing to develop a paediatric use for an off-patent drug may, voluntarily, submit a PIP to the PDCO for assessment. The results of an agreed PIP are then included in an application for a PUMA, which is a new type of marketing authorisation soley for the paediatric use of a product.

A PUMA can cross-refer to data contained in Marketing Authorisation Applications from any Member State, and/or can include bibliographical data, and this can be supplemented by any new paediatric data. This, and other, new paediatric research for off-patent drugs can be supported by community funds under the Medicines Investigation for the Children of Europe (MICE) initiative.

The format of all PIPs and/or waiver requests are similar. Note that for new indications, routes of administration and/or pharmaceutical forms, the PIP and/or waiver request must address all the existing indications, routes of administration and pharmaceutical forms, as well as the new ones. In addition, submissions that will be used to support PUMA applications must include waiver requests for paediatric age groups not covered by a PIP.

A PIP and/or waiver submission must be preceded by a Letter of Intent, which must be written according to a template and sent to the EMEA using Eudralink at least 2 months before the intended submission date. Assessments are undertaken according to published schedules and so a submission must be made by a specified date in order to enter a particular assessment schedule.

The introduction and Section A of the application are made using an electronic template. The remaining sections on scientific documentation should be word processed, with each condition being covered in turn, ideally in no more than 50 pages each (excluding references). The submitted package must be provided as hard copy and also electronically as PDFs (searchable where possible) and, where possible, Microsoft Word documents. A cover letter should be included and written according to a template.

Assessments are free of charge.

Within 30 days of submission: The EMEA must validate the submission. During this period, the EMEA may ask for a clock stop pending the provision of more information to enable validation. The date of submission of a validated application is Day 1

Day 30: During the first 30 days of the assessment, an assessment report prepared by the EMEA is reviewed by two members of the PDCO assigned to the project - the Rapporteur and the peer-reviewer. This report is presented to the PDCO at Day 30 and also provided to the Applicant

Day 60: During the second 30 days of the assessment, other members of the PDCO have the opportunity to review the assessment report and at Day 60 the whole PDCO must either (a) reach a positive or negative opinion about the application, or (b), in the case of a PIP with or without a waiver request, ask for modifications to the application. In the case of a full waiver request (across all indications and all paediatric age groups), the second option is not available. If a modification to the application is requested, the clock is stopped (ideally for no longer than 3 months) until the new information is provided. The clock restart is at Day 61.

Day 90: The assessment report is revised in the light of the revised submission, and presented to the PDCO and provided to the Applicant.

Day 120: The PDCO reach an opinion on the application.

Oral explanation: At any time during the assessment, the Applicant or the PDCO may request an Oral Explanation to discuss major issues.

After the opinion: Within 10 days, the EMEA informs the Applicant of the PDCO’s opinion. This opinion becomes final within another 30 days, unless the Applicant submits a written appeal against it, in which case the PDCO will review its opinion within 30 days, and this becomes final. Within another 10 days, the EMEA adopts the PDCO’s final decision.

An agreed PIP should not be considered as definitive and so should be revised if problems are encountered during its implementation. A revised PIP and/or a request for new waivers or deferrals will be reviewed, free of charge, by the PDCO within 60 days of submission. Their opinion is subject to appeal, as for the original submission (see Assessment of PIP/waiver submissions).

For any previously unauthorised medicinal products, and for patent-protected products being developed for use in new indications, routes of administration or pharmaceutical forms, the results of an agreed PIP must be submitted with applications for authorisation, unless the PDCO has agreed to a waiver or deferral. Otherwise, the application may not be validated. These obligations come into force on 26 July 2008 for new products and on 26 January 2009 for the other cases.

Patent-protected product: 6 month extension of the SPC, even if a paediatric indication is not granted. This reward is only granted if the product is authorised in all Member States. Also, the application for the SPC extension must be submitted at least 2 years before SPC expiry (although see Transitional arrangements for PIPs).

Orphan medicinal product: Additional 2 years of market exclusivity, even if a paediatric indication is not granted.

PUMA: Data/marketing protection according to the usual ‘8+2+1’ rule, including the additional year for products with significant clinical benefit.

Individual Member States can introduce additional incentives.

Recently-completed paediatric studies: Studies completed (= last patient, last visit) before the Paediatric Regulation came into force on 26 January 2007 can be included in the PIP, but will not be taken into account when considering eligibility to receive the exclusivity rewards.

Ongoing paediatric studies: Studies completed (= last patient, last visit) on or after the Paediatric Regulation came into force, and included in an agreed PIP, will be taken into account when considering eligibility to receive the exclusivity rewards, so long as they are ‘significant' studies. 'Significant' studies are usually expected to be in all relevant paediatric age groups and be of a certain type, such as placebo- or active-controlled efficacy studies, dose-finding studies, prospective clinical studies investigating a major safety issue, and studies concerning a new paediatric formulation.

Application for SPC extension: For the first 5 years after entry into force of the Paediatric Regulation, this need only be submitted prior to 6 months before SPC expiry.

Scientific Advice may be sought, free of charge, from the Scientific Advice Working Group (SAWG) on paediatric studies before or after submission of a PIP. Advice can also be sought on pharmacovigilance and risk management systems.

EU Paediatric Regulation (Regulation (EC) No. 1901/2006) and subsequent minor revisions (Regulation (EC) No. 1902/2006)

European Commission draft guideline on PIPs, waivers and related issues

EMEA site on paedatric medicines including the electronic template for PIP applications and waiver requests.