Dr Hession has a special interest in writing and advising on the EU paediatric investigation plan (PIP) and waiver and deferral requests.

The PIP is a key element in the EU Paediatric Regulation. It is a plan for adequately defining the efficacy and safety of most medicinal products across all paediatric age groups (namely preterm neonates, term neonates, infants and toddlers, children (aged 2-11 years) and adolescents) in conditions related to all proposed and approved indications.

The Paediatric Committee (PDCO) is the body within the European Medicines Agency (EMA) responsible for overseeing the requirements of the Paediatric Regulation. The PDCO may grant a waiver from developing a PIP for certain (or all) conditions and/or certain (or all) paediatric age groups, and/or a deferral of the start or completion of all or some of the studies (or any other measures) in the PIP. The PDCO grants 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, have been 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

Based on the latter article, and work on numerous PIP/waiver applications since their inception in 2007, Dr Hession has compiled a list of tips on how to write and revise the document to achieve a successful outcome.

• Review all relevant guidance (Paediatric Medicine section of the EMA website)
• Review previous Opinions of the PDCO
• To investigate a possible class waiver or successful strategies in similar conditions
• Use the EMA template (EMA/427403/2012) to write the scientific document (Parts B-E)
• This also provides good guidance on the content
• A high level of detail is required in a PIP/waiver application
• The requirements are different to those of the US Pediatric Study Plan and the Written Request
• Don’t repeat the same information in different parts of the application
• Consider obtaining expert help
• Consultants experienced in PIP strategy and writing
• Opinion leaders in the case of contentious issues
• Obtaining scientific advice on planned studies is useful
• Also a good way to engage with the PDCO at an early stage, due to their links with the Scientific Advice Working Party (SAWP)
• A pre-submission teleconference is helpful to review the validity of the application
• However, it is not a pre-assessment

• It is important to clearly define the relevant ‘condition’ and ‘indication’
  • A ‘condition’ is a recognised medical condition, whereas an ‘indication’ is a use (treatment, prevention or diagnosis), often in a subset of the condition
• The PIP/waiver must address the condition that encompasses the indication(s) being sought
• How to define the 'condition' is now determined by an EMA policy (EMA/272931/2011)

• Don't provide only a cursory analysis, particularly concerning paediatric disease
• It will not be accepted by the PDCO
• It will not provide a firm foundation on which to argue for any appropriate waivers
• Justify the selected ‘condition’ in Part B.1.1
• In Part B.2, only discuss either the diagnosis, prevention or treatment in paediatric populations, according to the sought indication

• Lack of data is not a valid reason for a waiver
• A waiver on the grounds of lack of significant therapeutic benefit is justified not only in relation to existing treatments, but can also include:
• Clinical studies are not feasible, e.g. for ethical or cultural reasons, or because of very low prevalence (although products with an orphan designation may be subject to a PIP)
• Paediatric needs are already covered
• New clinical trials are not expected to be of significant therapeutic benefit or fulfil a therapeutic need, e.g. because sufficient data are already available from paediatric studies
• If a full waiver is sought, the Opinion will be given at Day 60 with no option for the assessment to continue for another 60 days

• Don’t just reference the Investigator Brochure for a discussion of the development to date
• Include a summary in the PIP text (not just cut and paste from the Investigator Brochure)
• The summary of the proposed studies (and other measures) in the Key Elements Form will form the basis of the binding elements contained in the PDCO Opinion
• This must be carefully worded since every detail must be exactly adhered to for a positive compliance check
• Part D.2 – Quality aspects:
• Age appropriate formulations are expected and palatability studies are usually required if relevant
• Excipients can be an issue in children
• Part D.3 – Non-clinical aspects:
• The most usual required non-clinical study is a juvenile toxicity study
• Beware of performing it in a species in which relevant metabolic maturation occurs at a different developmental stage to that in humans
• Part D.4 – Clinical aspects:
• Use modelling wherever possible, for example population pharmacokinetic +/- pharmacodynamic modelling to enable sparse sampling
• Use of physiologically-based pharmacokinetic modelling is difficult due to often inadequate information on pharmacokinetics in adults and metabolic maturation in children
• A step-wise approach to the plan can be useful (for example, by age group, indication, study phases)
• It might be possible to move the follow-up of clinical trials into the Risk Management Plan

• A deferral means that the results of the deferred studies (or other measures) are not required for validation of the marketing authorisation application (MAA)
• It is not a delay in the submission of a PIP
• It is usual to defer the start of paediatric studies until human adult studies and any juvenile toxicity studies have been completed

• Communicate with the Paediatric Co-ordinator at the EMA if there are any queries about the assessment or requests at any stage
• The validation step can include requests for scientific changes, such as the nature of the ‘condition’
• However, failure to agree to requested changes will not necessarily prevent validation
• The comments in the Day 30 Summary Report may change significantly by Day 60
• The Day 30 assessment only represents the views of the Paediatric Co-ordinator, the Rapporteur and the Peer Reviewer, not the whole PDCO
• Almost all PIP/Waiver applications result in a Request for Modification (RfM) at Day 60
• Seek a teleconference with the EMA to clarify any queries (but not to define the response to the RfM)
• If the RfM suggests unfeasible studies, support their unfeasibility with data
• If the PIP/Waiver is significantly altered (e.g. submission of new data or accepting PDCO suggestions) this must be done in the response to the RfM, since after Day 61 this will not be possible
• The PDCO strongly discourage seeking scientific advice during the clock-stop (since the PDCO will ultimately provide the advice anyway)
• Consider requesting an oral hearing if isolated points of disagreement remain at Day 90
• Check the exact wording of the Opinion before it is finalised
• It may contain errors or unexpected changes and the exact wording will be used for the compliance check
• It takes approximately 6 weeks from when the Opinion is given until this is formalised in the ‘Decision’ (required for MAA validation)

• PIP modifications are common but are sometimes for reasons that could be avoided by better wording of the Opinion
• A compliance check is not required if the start of all the PIP measures is after the date of submission of the MAA
• It is ideal to keep paediatric studies off the critical path of the development programme, since the compliance check cannot be started until the relevant final study reports are available
• To avoid delays in MAA validation, the compliance check should be started at least two months before submitting the dossier