Mediplex has a special interest in writing paediatric investigation plans (PIPs) and requests for waivers and deferrals of PIPs, 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 EU Paediatric Regulation. It includes obligatory requirements. The PIP is a plan for adequately defining the efficacy and safety of certain medicinal products in all proposed and approved indications across all paediatric age groups (namely preterm neonates, term neonates, infants and toddlers, children (aged 2-11 years) and adolescents).

The Paediatric Committee (PDCO) is the body within the European Medicines Agency (EMEA) responsible for overseeing the requirements of the Paediatric Regulation. The PDCO may grant a waiver from submitting a PIP for 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, and any other measures, 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.

Summaries of two meetings on the Paediatric Regulation, written by Dr Hession and published in Regulatory Rapporteur:

• Paediatric Medicines (March 2007; 4 (3): 26-28): A summary of the Paediatric Regulation, together with various commentaries on it
• PIP Tips - Practical Advice on Paediatric Investigation Plans from a Recent Workshop (November 2009; 6 (11): 21-23): Advice on submitting PIPs and waiver/deferral requests, the assessment process, and checks for compliance with the PIP

Generally, it is obligatory to submit a PIP and/or a waiver request for the following types of medicinal products:

• Products that have not been previously authorised in the EU (whether patent-protected or not). This is called an 'Article 7' submission.
• Authorised 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. This is called an 'Article 8' submission. 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.

Companies wishing to develop a paediatric use for an authorised, non-patent-protected product may voluntarily submit a PIP, covering the selected indication(s), to the PDCO for assessment. This is called an 'Article 30' submission. The results of the agreed PIP are then included in an application for a PUMA, which is a new type of marketing authorisation solely 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 information can be supplemented by any new paediatric data. This, and other, new paediatric research for such drugs can be supported by community funds under the Medicines Investigation for the Children of Europe (MICE) initiative.

The same format is used for all PIPs and/or waiver requests. The format and required content are detailed in the European Commission guideline on PIPs, waivers, deferrals, and related issues. The format found in the PIP and waiver application form issued by the EMEA is slightly different, but this should be followed. A PIP or waiver request must cover all paediatric age groups. Furthermore, in an Article 8 submission, the PIP and/or waiver request must address all the existing indications, routes of administration and pharmaceutical forms, as well as the new ones.

• Name of active substance
• Product name or proposed name
• Proposed pharmaceutical form(s) for paediatric development
• Condition that is treated, prevented or diagnosed by the product in adults (and children, if a paediatric indication)
• Proposed paediatric indication corresponding to the condition
• Therapeutic indications in adults (and children, if a paediatric indication)
• Applicant
• Relationship of application to other PIP applications
• Language request for the final opinion of the EMEA on the application (called the 'Decision')
• Declaration
• Whether the application concerns a PIP (including any requests to defer its provisions) and/or waiver requests, and information on any waiver requests

Part A: Administrative and product information

• Applicant details and contact details
• Type of medicinal product
• Name of active substance and strengths
• Pharmaceutical form(s) and route(s) of administration
• Relevant clinical trials
• Marketing authorisation status of product
• Relevant regulatory advice received
• Any orphan drug designation
• Planned date of application for Marketing Authorisation, Variation or Line Extension
• List of attached administrative annexes, e.g. Scientific Advice, latest SPC
• Translation of certain terms (if the EMEA Decision is requested in a language other than English)

Part B: Overall development of the medicinal product including information on the target diseases/conditions

• How each conditions differs between the different paediatric age groups and between these and adults
• The prevalence/incidence of each condition in different paediatric age groups, including the earliest age of onset
• Summary of the basic pharmacology of the drug
• Current methods of diagnosis, prevention or treatment (as relevant to the proposed indications) of each condition in the paediatric population
• Whether the product is expected to address an unmet therapeutic need or provide a significant therapeutic benefit over existing products

Part C: Applications for product-specific waivers

• Likely lack of efficacy or safety of the product
• A condition does not occurs in certain age groups
• Lack of significant therapeutic benefit of the product over existing products. This provision also allows for a waiver on the grounds of lack of feasibility of clinical studies and that adequate clinical data are already available

Part D: Paediatric Investigation Plan

• Overall strategy, including up to date summary of quality, non-clinical and clinical data that are relevant to paediatric development, and planned studies in adults. Often in the form of an Investigator Brochure.
• Strategy regarding quality issues
• Outline of each study/step in the development of a paediatric formulation
• Non-clinical strategy
• Summary of all planned/ongoing non-clinical studies
• Outline of each non-clinical protocol
• Clinical strategy
• Summary of all planned/ongoing clinical studies
• Outline of each clinical protocol
• Timelines of PIP

Part E: Request for deferral(s)

• Adult studies should be conducted first
• Paediatric studies will take longer to perform than adult ones

Part F: Annexes

• Literature references
• Investigator Brochure

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 electronically as PDFs (searchable where possible) and, where possible, Microsoft Word documents. A cover letter should be included and written according to the template provided.

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 a Paediatric Coordinator at 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. A positive Opinion for a PIP includes binding measures, such as certain studies that must be performed.

Meetings/Teleconferences: At any time during the assessment, the Applicant or the PDCO may request an Oral Explanation to discuss major issues. In practice, this rarely occurs, but it is quite common to have a teleconference with the EMEA to discuss a request for modification.

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 Opinion, which is then called the 'Decision'.

An agreed PIP should not be considered as definitive and so should be revised if problems are encountered during its implementation. This is particularly the case if changes to the programme affect the key binding measures, such as studies, listed in the PDCO Opinion, since the PIP will fail its compliance check if these measures are not achieved (see Submitting the results of a PIP, and compliance check).

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 (Article 7 submissions), and for patent-protected authorised products being developed for use in new indications, routes of administration or pharmaceutical forms (Article 8 submissions), the results of an agreed PIP must be submitted with applications for authorisation, unless the PDCO has agreed to a deferral or a full waiver. Furthermore, it must be confirmed that all the key binding measures in the agreed PIP, as specified in the PDCO Opinion, were complied with. If a required PIP is not submitted or fails the compliance check, the application will not be validated.

Rewards for complying with an agreed PIP are only granted once for each product, and not until any agreed deferred measures have been completed and have passed the compliance check

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 Party (SAWP) on paediatric studies before or after submission of a PIP. Advice can also be sought on pharmacovigilance and risk management systems.

Seeking Scientific Advice is a good way to engage the PDCO early in the development of a PIP, since the PDCO and SAWP have a close working relationship.

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

European Commission guideline on PIPs, waivers, deferrals, and related issues

EMEA site on paediatric medicines including the PIP and waiver application form