Navigating the Paediatric Investigation Plan and its Significance in the Development of Medicinal Products.
The development and authorization of medicinal products for paediatric use are essential for ensuring the health and well-being of children. However, conducting clinical trials involving children requires a distinct set of considerations and ethical standards. To address these challenges, the concept of a Paediatric Investigation Plan (PIP) was introduced. It serves as a pivotal tool in the research and development process for paediatric medications.
What is a Paediatric Investigation Plan (PIP)?
A Paediatric Investigation Plan (PIP) is a comprehensive strategy and document that outlines the necessary steps to gather paediatric data. This is necessary for the authorization of medicinal products specifically for children. PIPs are typically submitted early in the product development phase. This follows human pharmacokinetic (PK) studies in adults. These plans undergo rigorous evaluation by the Paediatric Committee (PDCO) of the European Medicines Agency (EMA).
The landscape of drug development is dynamic, and it’s not unusual to encounter scientific uncertainties when initially assessing a PIP. In such instances, adjustments to the plan become necessary to align with evolving knowledge. To tackle this challenge, a collaborative effort involving representatives from the pharmaceutical industry, EMA, and PDCO resulted in the development of the ‘Stepwise PIP’ (sPIP) concept. This framework simplifies the process of reaching a consensus on a PIP, allowing certain elements to remain open for refinement as more scientific evidence becomes available. It incorporates essential data and completion dates based on the current state of scientific knowledge, with subsequent modifications following agreed-upon milestones and timelines.
Efforts have been put forth to improve the efficiency of the PIP process. Key elements within PIP opinions have been revised to prioritize crucial details, and the PIP summary report template has been updated accordingly. Administrative submission requirements for PIP applications and procedural aspects of PIP compliance checks have been streamlined to ensure a more seamless process.
Deferrals: Postponing Paediatric Studies
Deferrals are an essential component of paediatric drug development. They allow applicants to postpone conducting paediatric studies until sufficient evidence proves the safety and effectiveness of the medicine in adults. Even when deferrals are granted, the PIP still includes specific information about planned paediatric studies and their timelines. Importantly, deferrals enable applicants to submit a regulatory application for the medicine’s use in adults, even if studies involving children have not been initiated or completed. Studies involving children can be initiated or completed after applying for marketing authorization for adult use.
Waivers: Exemption from Paediatric Studies
Waivers may be granted for the development of a medicine in children under specific circumstances. Medicines may be exempt from the requirement to submit a PIP if they are not necessary or not suitable for paediatric use. This applies to diseases that only affect adults, medicines intended for such conditions, or those that do not provide significant therapeutic benefits compared to existing paediatric treatments.
Annual Reports on Deferrals
MAHs who have been granted deferrals within a PIP are obligated to submit annual progress reports to the relevant regulatory agency. These reports provide updates on the advancement of paediatric studies, aligning with the agency’s prior approval of the PIP and its deferral provisions. The timing of these reports is contingent upon the specific circumstances and timeline of the PIP decision.
For newly authorized medications that have an established PIP with an associated deferral:
- The initial annual report should be forwarded to the regulatory agency during the month preceding the first anniversary of the date when marketing authorization was granted.
- There is no obligation to submit annual reports before the marketing authorization is officially granted.
For medications that are not newly authorized:
- Should the PIP decision be reached fewer than six months before the first anniversary of the initial marketing authorization within the European Economic Area (EEA), the MAH is required to submit the annual report during the month preceding the following marketing authorization anniversary.
- In cases where the anniversary date occurs more than six months after the PIP decision date, the report should be forwarded in the month prior to the anniversary date.
Technical Requirements for PIP Applications
When submitting PIP or waiver applications electronically, several technical requirements must be adhered to:
While not recommended, if the applicant chooses to use password protection or other security settings for Word files, they must communicate the password to the Agency. This is to ensure that the Agency can access and work with the content, such as printing, selecting text, and copying it into another application.
Do not include internal or external hyperlinks to websites, references, tables, or pictures within the documents.
Whenever possible, avoid scanning physical documents or generating PDF image files. If the applicant must scan a document that’s only available in paper form, ensure that the scanned version is legible both on-screen and when printed. The recommended scan resolution is 300 dots per inch (dpi) in black and white, which balances legibility and file size.
Follow the naming convention provided in the PDF icon Guidance on paediatric submissions for all files. Avoid merging application forms into a single PDF file. For referenced publications, use single files (one per reference) and name them by the first author and year (e.g., ‘Smith PH et al 2004.pdf’). Keep file names concise.
Alphabetical Order for References
In the reference list (part F of the submission), arrange references in alphabetical order based on the first author’s surname.
Provide all documents in electronic format, including the investigator’s brochures and the risk management plan (if applicable). This ensures that all components of the submission are easily accessible electronically.
The Paediatric Investigation Plan (PIP) is a vital component in the development and authorization of medicinal products for children. It ensures that paediatric data are collected and evaluated to determine the safety and effectiveness of medicines in this vulnerable population. Through deferrals and waivers, flexibility is introduced to cater to the dynamic nature of drug development while maintaining the highest standards of paediatric care. By adhering to technical requirements and streamlining processes, the pharmaceutical industry, regulatory agencies, and healthcare providers are working together to advance paediatric drug development, ultimately benefiting the health and well-being of children worldwide.
At DDReg, our team comprises seasoned experts that provide end-to-end regulatory affairs and medical writing services. Our knowledgeable consultants are well-equipped and have extensive experience of global requirements of agencies to guide you when navigating the nuances of PIPs and other documents that support clinical development of products. For over 14 years we have provided our customers with tailored regulatory, pharmacovigilance, medical affairs, intellectual patent services, and more that apply throughout the product’s lifecycle- from development phase to post-approval phase for regulated and emerging markets. Our medical affairs capabilities also cover regulatory writing including documents for eCTD (Non-Clinical and Clinical Overviews & Summaries) and pharmacovigilance (Risk Management Plans, Periodic Reports, etc).
References and Further Reading
- Paediatric Investigation Plans European Medicines Agency. 2023
- Paediatric Investigation Plans: Questions and Answers European Medicines Agency. 2023
- PIP Assessment Procedure European Medicines Agency. 2023