Ask the Expert: Mette Due Theilade Thomsen, Ph.D.

Q: In your experience, what has been the main driver for sponsors not seeking or deferring the Pediatric Investigational Plan (PIP) process in a gene therapy setting?

A: A lack of understanding regarding PIP requirements, including the legal obligation to submit the PIP early in the development process, remains a significant challenge. Additionally, gene therapies, which often target pediatric populations exclusively, present further difficulties for companies.

Many find it challenging to prepare and submit a PIP by the time of the first human dose, given the complexity, and early-stage nature, of these programs. The sophisticated science behind gene therapies, combined with the need to establish manufacturing processes and safety profiles, creates a demanding timeline that many sponsors struggle to meet.

Q: How do companies best prepare for the EMA PIP submission process if unfamiliar with European regulatory procedures?

A: The EMA offers guidance and interaction opportunities for small or medium-sized companies, including those with Priority Medicine (PRIME) designation, to support medicinal product development. The EMA pediatric website provides detailed resources for PIP submissions, including templates and instructions.

You can also submit questions via an online inquiry form, which are directed to the pediatric team. Once your PIP draft is nearly complete, you can request a pre-submission meeting with the EMA to obtain guidance on ensuring a smooth validation.

Attending a training course, such as the PIP Training Course run by the Drug Information Association (DIA), is also helpful. These courses provide practical insights into the submission process and help companies understand the regulatory expectations.

Q: What is the EMA's new "stepwise PIP" (sPIP) approach, and how might it benefit US companies developing pediatric therapies?

A: The sPIP is still in a pilot phase, which involves the EMA testing eight different PIPs for innovative medicines that are at an early stage of development, when little is known about the details of the development program.

The sPIP will, in the future, allow for PIPs that, in the first submission, include less binding information on the pediatric trial compared to what EMA has traditionally expected. The initially missing information will then have to be provided later via PIP modifications, the timing of which should be agreed upon during the initial PIP submission.

This approach is particularly beneficial for gene therapies and other innovative treatments where the full development strategy may not be clear at the time of initial submission. It provides more flexibility while maintaining the regulatory framework necessary to ensure pediatric development.

Q: Could you provide insight into how the Pediatric Committee determines and evaluates specific requirements for PIPs, especially for therapies targeting rare pediatric conditions?

A: A PIP is required even for orphan medicines, and it should include a plan for the studies needed to obtain a pediatric indication. For very rare diseases, maximizing limited study material is crucial, often through strategies like modeling and simulation, extrapolation, or using external controls such as historical data or registries.

Pediatric trial designs must be carefully tailored and often differ from adult trials. Endpoints should be relevant to, and validated for, the pediatric population, with primary endpoints typically demonstrating efficacy rather than focusing solely on safety.

For complex PIP scenarios, the EMA often expects consultation with pediatric research networks (e.g., EnprEMA) to ensure the feasibility and appropriateness of the trial design. In recent years, EMA has shown greater flexibility regarding the binding measures in the PIP key elements form, allowing certain elements to be decided later when more data is available.

In such cases, a PIP modification will often be required to update the plan with the additional information. This flexibility is particularly important for rare pediatric conditions where traditional development paradigms may not apply.

Q: What strategies do you recommend for industry sponsors to align their PIPs with international pediatric plans to streamline global development efforts?

A: The differences between agencies in terms of requirements and expectations for pediatric study plans are no longer pronounced because the EMA and FDA have worked to align over the years. The most significant difference is that in the US, orphan medicines are exempt from the Pediatric Study Plan (PSP) requirement (except for molecularly targeted pediatric cancers). In contrast, there is a legal requirement to submit PIPs regardless of orphan status in Europe.

Concerning submission timing, it is recommended that PIPs and PSPs be submitted simultaneously because the EMA and FDA will then work to align their requirements at their monthly pediatric cluster meeting – they have mutual confidentiality agreements and exchange information on PSPs and PIP. Therefore, one should strive to include the same information in the two documents, which can be done efficiently because the two agencies expect the same information to be included.

Pediatric cluster meetings held monthly between the EMA, FDA, Health Canada, PMDA (Japan), and TGA (Australia), enable global alignment. Since Brexit, the UK's MHRA also requires a PIP. It's recommended that the same information included in the EU PIP should be included in the UK PIP, with UK-specific details on unmet needs added. The UK PIP should be submitted after the EU PIP is agreed upon. This streamlines the process with MHRA, which strives to align with the EMA but currently lacks a mutual information-sharing agreement with the EMA.