EMA Guidance on Paediatric Investigation Plans

On 6 Feb. 2023, the European Medicines Agency (EMA) issued new European Union (EU) guidance for drug developers regarding the conduct of paediatric investigation plans (PIPs), particularly when clinical information is limited (1). EMA defines a PIP as “a research and development programme aimed at ensuring that the necessary data are generated determining the conditions in which a medicinal product may be authorized to treat the paediatric population” (1). Ideally a PIP should be submitted to the Paediatric Committee (PDCO) at the EMA following pharmacokinetic studies in adult humans and are reviewed under regulation (EC) No 1901/2006 (Paediatric Regulation) (2) and regulation (EC) No 19032/2006 (Paediatric Regulation) (3).

In 2017, the European Commission (EC) published its 10-year report on the implementation of paediatric regulation where it highlighted five areas that remained a challenge or lagged behind adult regulations. These included identifying paediatric medical needs, strengthening of cooperation of decision makers, ensuring timely completion of PIPs, improving the handling of PIP applications, and increasing transparency around paediatric medicine (4).

Steps taken to address shortfall in paediatric regulation

To address these issues, the European Federation of Pharmaceutical Industries and Associations (EFPIA) and European Forum for Good Clinical Practice (EFGCP) organized a multi-stakeholder workshop with EMA in 2019 to help define paediatric unmet medical needs (5). Furthermore, Accelerate, in collaboration with EMA, held various meetings on topics related to children and adolescent therapies (6), and the results of these interactions were published in the scientific literature to raise awareness.

Similarly, EMA’s Paediatric Committee (PDCO) strengthened its collaboration with the Clinical Trials Coordination Group (CTGC) and improved harmonization of pedantic regulations through EMA/US Food and Drug Administration cluster activities (7) and establishing the EMA/PDCO PIP assessment process. The European network of paediatric research and EMA (Enpr-EMA) also established an international working group to work on a white paper to provide recommendations on international standard for sustainable paediatric clinical trial sites (8).

In terms of ensuring timely completion of PIPs, EMA published a reflection paper in 2018 on the use of extrapolation in the development of medicines for paediatrics (9) and the Enpr-EMA published a framework about paediatric clinical trial preparedness in 2020 (10). This framework provided developers with further clarity around the extrapolation of data and additional guidance on the implementation of paediatric clinical trials.

Piloting of stepwise PIP approach

To improve the handling of PIP applications, the EMA/PDCO has developed a framework for a “stepwise PIP” (sPIP) approach, which aims to simplify the administration of PIP submissions and procedural aspects of PIP compliance and allows changes to be made to PIPs as more evidence becomes available (1).

On 6 Feb. 2023, EMA launched the sPIP pilot programme, and eight sPIPs are due to be adopted and opinions gathered to help mould the process and inform decision-making for its future use. At the current time, EMA does not anticipate a sPIP approach will be warranted in most cases, but a dedicated pre-submission meeting with the Paediatric Medicines (PME) Office is recommended to determine if an sPIP approach is justified (1).

However, a sPIP submission may be justified in cases where there is limited scientific knowledge, for instance, the development of a first-in-class drug to treat a rare paediatric disease, when the mechanism of action of a drug is not fully characterized and may impact ontogeny-related changes in an individual or a medicine addresses significant unmet needs in several indications where adult data are lacking. Applicants may participate in the sPIP pilot programme on a voluntary basis and may consider this option if the study design, population, and main objectives of a study are not well‑defined (1).

When a developer chooses to submit a sPIP they do so using the same template as a conventional PIP but the content included in part B and D will differ.

Part B includes:

• a valid scientific justification to support a sPIP approach in the development in all paediatric ages or in certain age subgroups
• information and explanation regarding information gaps and why some studies cannot be planned or aspects of the clinical studies cannot be determined or estimated at the time of the initial application
• a detailed discussion on existing information (or lack thereof).

Part D includes:

1. a high-level, overall plan and strategy for paediatric development (e.g., the condition, preliminary outline of planned studies based on available evidence and a PIP completion date)
2. milestones/timelines for subsequent PIP modification(s) and outline of how the missing data will be generated and the PIP fully completed
3. open sections to discuss and agree future modification procedures to develop the final full PIP.

If additional information becomes available during the sPIP, the application can be modified via the established modification procedure used in the traditional PIP approach. Not all elements need to be modified at the same time, but multiple modifications should be avoided and streamlined/or bundled where appropriate. If applicable, timelines/milestones can be updated during the modification procedure. In cases where significant updates to the sPIP are requested, a pre-submission meeting with the PDCO assessment team is strongly recommended. The same compliance checks apply to sPIPs as conventional PIPs.

The EMA is also working to increase transparency around paediatric medicines and is updating the Community Register of medicinal products with paediatric information and a public register regarding paediatric trials is under development.

Future implications

It is clear that EMA has taken great strides to address the challenges and areas of paediatric medicines that lagged behind adult medicines. The implementation of sPIPs is one way to promote paediatric drug development and better aligns the data requirements between decision-makers and the regulators. The sPIPs should enable developers to move paediatric medicines forward with a minimum set of data and allow sPIPs to be refined as more data becomes available.

Overall, the EMA-EC paediatric plan taken together with the Orphan Drug Regulation should help to provide a framework to improve the implementation of Paediatric Regulation where all stakeholders can collaborate and help to improve the efficiency of the process so that developers continue to target areas of high unmet medical need and increase the number and speed to market of paediatric medicines that can benefit future generations.

References

1. EMA. EMA/768685/2022, Guidance for Stepwise PIP Pilot (6 Feb. 2023).
2. EMA. Regulation (EC) No 1901/2006 of the European Parliament and of the Council on 12 December 2006 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 (December 2006).
3. EMA. Regulation (EC) No 1902/2006 of the European Parliament and of the Council of 20 December 2006 Amending Regulation 1901/2006 on Medicinal Products for Paediatric Use (December 2006).
4. EMA. EMA/635567/2022, Boosting the Development of Medicines for Children (6 Feb. 2023).
5. Joint EFGCP EFPIA. EFPIA and EFGCP Multi-stakeholder Workshop on Paediatric Unmet Medical Needs, 12 Dec. 2019.
6. ACCELERATE. ACCELERATE Platform—Innovation for Children with Cancer. Accelerate-platform.org (accessed 20 Feb. 2023).
7. EMA. FDA/EMA Common Commentary for Submitting an Initial Pediatric Study Plan (iPSP) and Paediatric Investigation Plan (PIP) for the Prevention and Treatment of COVID-19. EMA.europa.eu, 2 June 2020.
8. EMA. European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA). EMA.europa.eu (accessed 20 Feb. 2023).
9. EMA. EMA/189724/2018, Reflection Paper on the Use of Extrapolation in the Development of Medicines for Paediatrics—Final (7 Oct. 2020).
10. EMA. EMA/56009/2019, Preparedness of Medicines Clinical Trials in Paediatrics (13 Aug. 2020).

About the author

Cheryl Barton is director of PharmaVision, info@pharmavision.co.uk

Article details

Pharmaceutical Technology Europe
Vol. 35, No. 3
March 2023
Pages: 7–8

Citation

When referring to this article, please cite it as Barton, C. EMA Guidance on Paediatric Investigation Plans. Pharmaceutical Technology Europe, 2023, 35 (3), 7–8.