by Linsey Reavie
In order to receive approval for a marketing authorisation application (MAA) in the European Union, Sponsors must present a European Medicines Agency (EMA) Paediatric Committee (PDCO) approved paediatric investigation plan (PIP) for their product (No/1901/2006, 2006).
Importantly, the PIP must consider the potential paediatric need for clinical development in all paediatric subsets as defined by the EMA (Table 1).
Depending on the product type and its disease relevance in different paediatric subsets, the Sponsor can request a waiver, a deferral and/or propose a paediatric clinical study. By nature the paediatric population is very diverse, and it is therefore easy to imagine that the paediatric need can significantly vary within a single indication for a specific product.
Below are 5 key tips to consider when preparing the PIP application.
1) Define the PIP strategy early in the writing process.
It is important to carefully consider the most relevant condition and indication for your product in the entire paediatric population. This requires a comprehensive understanding of the paediatric disease landscape and of the potential risk/benefits of your product within all subsets.
According to the EMA guideline, the condition is identified based on the proposed adult indication, the products mode of action (MoA), an independent hierarchical classification of diseases and conditions (e.g. the MedDRA dictionary) and, most importantly, an unmet paediatric need (EMA/272931/2011).
While it is likely the paediatric indication will be similar to what is proposed in adults, it does not have to be identical.
Consult the MedDRA dictionary to identify the higher level term (HLT) that best fits the proposed condition and indication realizing that all preferred terms (PTs) under that HLT that could benefit from the product (based on its MoA and unmet need) could also be considered by the PDCO for paediatric development.
The greatest unmet paediatric need is the basis by which the PDCO determines the most appropriate condition for paediatric development with your product. Thus, if another PT is more suitable than what has been proposed, the PDCO could ask for development of the product in that PT in addition to the proposed PT (e.g. indication).
The earlier these points are considered the easier it is to identify where a PIP waiver, deferral and/ or proposed clinical study are most appropriate for the proposed paediatric indication.
2) Consider the future development plans for your product.
Understand the entire scope of the development program in adults as well as children that are currently ongoing or will be developed (within reasonable time frame). PIP applications must be submitted after the first in man study and before Phase II studies for each potential indication. For a single product, the development timelines for all clinical plans must be considered in terms of how that dictates PIP submission(s).
If the development plans are somehow overlapping (e.g. by an overarching disease like autoimmunity) this could impact:
The identified condition for the PIP application. The condition is based on a HLT that can include multiple indications that, for the product, could be under current or future development.
The indication for the paediatric population. Whether the product will be used as first line or second line therapy for individual development programs could differentially impact individual PIP strategies. All PIP applications must be aligned in how they present the product in terms of development information and risk/benefit to the entire paediatric population.
The number of PIPs required for the product. In the above example, perhaps two different indications could be covered under one HLT in a single PIP.
Lastly, if the clinical development program is extensive, ensure alignment of positions across all PIP applications.
3) Consult the EMA website for approved PIPs that have set a precedent for your desired condition and indication.
PIP opinions are available on the EMA website and can be quite helpful to identify if the PDCO has reviewed a PIP with a similar product or concerning a similar indication. The summary of the opinion can help to outline the PIP strategy and understand how the PDCO might view the paediatric need in a particular indication/condition.
4) Identify any and all potential risks for your product that are relevant for the paediatric population
As already mentioned, the pediatric population consists of children at all developmental stages, sizes and capability. On its own, the diversity within the paediatric population can make outlining a clear PIP strategy challenging and complex. A few tips to get started are:
Perform a deep dive into the paediatric literature for the disease at all stages
Understand the MoA of the product (as best as possible)
Be aware of the developmental differences in organ systems at all developmental stages. EMA has outlined the current understanding of this with more details in the guideline (EMEA/CHMP/SWP/169215/2005, 2008)
5) Ensure there is a solid scientific basis to justify all requests within your PIP.
There are real and important reasons to consider if development of a specific product is appropriate in the paediatric population. They are an inherently vulnerable group that should be carefully protected from any undue harm potentially induced by treatment with novel therapies. Equally important, however, is the need to properly develop products for paediatric use. Therefore, when considering the need for a waiver or deferral, there must be a solid scientific basis for this request that is supported by scientific literature and clinical treatment guidelines etc. It is not sufficient to merely say “the disease does not occur in this subset” or “there is a lack of therapeutic benefit over existing therapies.” Instead, a thorough presentation of the disease prevalence (e.g. using EU relevant literature and calculations) of such a disease must be written. Similarly, a comprehensive presentation of current treatment methodology and a scientific basis for why the product is unlikely to provide a benefit should be presented through the use of published scientific literature demonstrating such claims.
Biopharma Excellence has been involved in assisting clients throughout all stages of the PIP process including submission through the eSubmission Gateway system. Biopharma Excellence would be pleased to assist you in any aspect that would be of interest. Do not hesitate to contact us [LINK zu CONTACT] for more information.
EMEA/CHMP/SWP/169215/2005. (2008). Guideline on the need for non-clinical testing in juvenile animals of pharmaceuticals for paediatric indications. London: EMA committee for human medicinal products
No/1901/2006, E. (2006). Regulation (EC) No 1901/2006 of the European Parliament and of the Council on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004.