In my 35 years of working to develop safer, more effective medications for children, I’ve often been asked about how to navigate the regulatory landscape in the US and Europe. In a previous blog post, I discussed the latest FDA trends regarding pediatric drug development. In this blog, I’ll focus on the path for achieving regulatory approval from the European Medicines Agency (EMA).
Like the US, the EU provides incentives to perform pediatric drug development and penalties for failing to do so. The EU provides a “carrot” by granting sponsors an additional six months of market exclusivity. A “stick” lies in tying a sponsor’s market authorization of the adult indication to having an approved pediatric development pathway. However, companies not adhering to these regulations haven’t been penalized. So, these penalties have mainly served as scare tactics. In addition, if you don’t attain an approved, agreed upon pediatric investigation plan (PIP), European legislation includes provisions for fining a drug company five percent of all their European drug sales. So, it’s wise to consider these requirements when developing your regulatory strategy.
European regulatory framework
Contrary to popular opinion, the EMA is not an FDA for Europe. They are the operational arm for the European Commission, which was mandated by the European Parliament to oversee drug development. The 28 member states, with the exception of the UK, have pooled their sovereignty to authorize the development of medicines for children. The EMA coordinates the existing scientific resources of the member states. Every country has the right to submit an individual to sit on the Pediatric Committee (PDCO), who will evaluate your drug and then help guide you towards a successful path.
The goal of the EMA is to improve the health of children globally by increasing the availability of well-characterized pediatric medications. Obviously, this requires performing high-quality, ethical research on children. And they want to achieve this goal without performing unnecessary pediatric studies or delaying authorization for adults.
The pediatric investigation plan
Pediatric drug programs face regulatory requirements at various phases in their development in both the US and for Europe. In the US, you should file your Initial Pediatric Study Plan (PSP) at the end of Phase 2 studies (EOP2). However in Europe, you file an agreed upon PIP at the end of your Phase 1 meeting where you’ve assessed your drug’s pharmacokinetic profile in adults. While your drug program moves through Phase 3, your PIP may undergo modifications.
The pre-PIP teleconference
The purpose of the pre-PIP teleconference is to ensure a smooth validation and subsequent PIP procedure. The scientific documents supporting the PIP are not assessed at this meeting. To maximize meeting productivity, I recommend bringing a list of questions to be discussed and having your draft application as complete as possible.
The content and timeline of the PIP
The PIP provides an overview of a pediatric drug’s development path. It includes an overview of the disease, the biological product, and any planned extrapolation to a specific pediatric population. The PIP also contains any requests for drug-specific waivers or deferrals for pediatric studies. Lastly, it details the summary and timeline of planned nonclinical and clinical studies in both adults and children as well as information on developing pediatric formulations.
The PIP’s major milestones are the following:
- Day 1: The clock starts ticking after the Validation Summary Report is issued. The validation checks whether the forms were completed, the structure of the application is correct, and enough scientific information and references are provided.
- Day 30: The first PDCO discussion summarizes the assessors’ opinion on the PIP so far. No actions by the sponsor is required at this point.
- Day 60: At the second PDCO discussion, they either adopt the opinion or request modification to the PIP. At this point, the clock is stopped for about three months before restarting again.
- Day 61: The PDCO provides an update to their summary report.
- Day 90: At the third PDCO discussion, the assessors provide a summary of their opinion on the updated PIP which can include minor requests.
- Day 120: After an oral explanation by the sponsor, the PDCO issues their final opinion (either positive or negative) on the PIP. Sponsors have until this point to withdraw their application.
Surprisingly, only about 11 percent of PIPs and PSPs are filed simultaneously. But, many technical aspects of a PIP can be repurposed for the PSP. Thus, I recommend to sponsors that they initiate a PIP and PSP in parallel to save time and costs.
The way forward
Pediatric drug development is increasing globally. To be successful, sponsors must develop robust regulatory strategies for both the EU and the US.
To learn more about addressing the challenges of pediatric drug development from both a practical and scientific perspective, please watch my webinar. Let me know what you think in the comments section!