For the purpose of this study, the list of off-patent active substances studied in an FP7-funded project (Area 4.2-1 Responding to EU policy needs: Off-Patent Medicines for Children) was taken into account, as previously reported (12). A total of 24 active substances were analysed covering 10 therapeutic areas in all paediatric age groups.

Therapeutic indication(s) for each active substances retrieved by national and centralised MAs were compared to those developed within FP7 projects, including target population and age subsets. As no official definition of repurposing exists, repurposing was considered if a new therapeutic use for the active substances was envisaged (1). This also aligns with innovative pharma companies definition on repurposing (see text footnote 2).

Thus, the following cases were considered as repurposing:

For the survey data, a descriptive analysis was conducted to summarise the collected information. This included indicating relative and absolute frequencies for each of the following categories:

The study does not foresee the processing of personal data, except for the specific contacts details (i.e., full name and email address) of people interviewed for each project, which are publicly available on the CORDIS database. Personal identifiers were not disclosed, nor made available to third parties. Consent was obtained to respondents before completing the questionnaire to process the above-mentioned personal data, and only non-confidential aggregated information was reported.

Data collection of PIPs, MAs variations/PUMAs and consulting of national databases was performed from May 1st to June 30rd, 2024. All the MAs and PIPs granted until June 30rd 2024 were analysed. The survey for project coordinators/reference persons was conducted from May 16th to July 18th, 2024.

At the time of this analysis, all the 20 projects were officially concluded, in a time range spanning from August 2011 to July 2020. The projects studied 24 off-patent active substances of chemical origin. Among these, 18 (75%) active substances were studied according to a PIP agreed by the PDCO from November 2010 to November 2015, submitted in the framework of these projects (see Table 1).

For bumetanide, no PIP was finally agreed, due to the project consortium decision to divert attention to more promising development pathways, based on preliminary results obtained. For ciprofloxacin and fluconazole, the initial PIPs were not pursued further due to study modifications requested by the PDCO, that were deemed not feasible. The PIP for metformin was discontinued due to commercial reasons (Table 1).

Positive compliance check was granted from the PDCO for 3/18 PIPs (16.6% of agreed PIPs), including dopamine, enalapril, and hydrocortisone. Successful conclusion of these PIPs resulted in three new PUMAs granted at centralised level, hydrocortisone granules (Alkindi^®), enalapril maleate (Aqumeldi^®), and dopamine hydrochloride (Neoatricon^®). Approval details on the PUMAs are available in Table 1.

A MAA (marketing authorisation application) for 6-mercaptopurine was withdrawn from the applicant as a similar product, having the Orphan Drug status, was granted a European MA in parallel and it was not possible to establish superiority.¹⁸ Further details on this specific case are reported in section “Challenges of conducting paediatric development plans.”

As off-patent medicinal products, all 24 active substances studied in the projects were approved at national level in at least one country considered in the analysis. Ten out of 24 active substances were also authorised at centralised level in EU. Six out of 24 (25%) active substances had an active OD at EU level for the same condition studied in the FP7 paediatric development plans. Three out of 24 (12.5%) development plans intended to study paediatric-only diseases, all including neonatal population. Details of the approved indications at centralised/national level are included in Supplementary Table 1.

According to the adopted definition, 22/24 (91.6%) paediatric development plans foreseen by FP7 projects could be classified as repurposing, as follows:

Remarkably, more than one half (12 out of 22, 54.5%) of these repurposing development plans involved neonates, targeting diseases with no approved treatments and relying heavily on off-label use for management. Further details are available in Table 2 and in Supplementary Table 1.

Out of 20 inquiries in the survey, 19 (95%) coordinators/reference persons responded, indicating the status and the challenges of running paediatric development plans for off-patent medicines under the FP7 framework.

The survey results showed that 14/19 respondents (73.7%) declared their projects were concluded, 3/19 (15.8%) were still ongoing, while 2/19 (10.5%) did not start.

Among the concluded projects, 10/14 projects (71.4%) concluded the clinical phase, 3/14 (21.4%) projects stopped at the pharmaceutical development/manufacturing phase, and 1/14 (7.1%) was stopped at the registration phase. The latter refers to 6-mercaptopurine, whose MAA dossier for a new age-appropriate formulation was blocked at registration due to the concomitant registration of a similar product by a competitor.

Fifteen out of 19 (78.9%) respondents reported that a pharmaceutical company or SME, committed to apply for MA for the paediatric medicine, was involved in the consortium. However, details about their specific role and involvement in the projects were not provided. Financial difficulties faced by SMEs were also cited as challenges impacting the successful progress of these research programs.

In terms of challenges encountered during the paediatric development programs, the most frequently reported challenges were budgeting (8/19) and the long regulatory/ethics approval process for paediatric trials (8/19). Recruitment challenges were the next most common (7/19). Challenges with drug supply and complying with PDCO requests were cited by 6/19 respondents. The development of age-appropriate drug formulations was identified by 5/19 respondents. Safety and efficacy issues, along with complying with national Competent Authorities (CAs) and/or Ethics Committees (ECs) requests, were mentioned by 4/19 respondents each. Trial sites activation was noted by 3/19 respondents, while project partners coordination and the conduct of non-clinical studies were reported by 2/19 and 1/19 respondent(s), respectively (Figure 1). Purely scientific issues were not reported. Further explanations were provided about the following items:

These challenges affected the conduct of studies included in PIPs agreed at the EMA/PDCO level. Indeed, 7/19 (36.8%) respondents declared they needed to ask for modifications to agreed PIPs. The main reasons for PIPs modification were mainly identified as difficulties in adhering to the scheduled timelines and challenges in reaching the enrolment target (Figure 2).

In terms of net results, three out of 20 projects succeeded in obtaining a PUMA for new paediatric medicines at centralised level. Although these results may be perceived as limited, representing a success rate of 15%, the following aspects need to be considered. First, two out of these three PUMAs were obtained in the last 2 years, more than 5 years after the formal completion of the project. So, other successfully completed projects could result in additional PUMAs in the future. Secondly, since the entry into force of the Paediatric Regulation, only nine PUMAs have been granted at EU level,²⁴ thus those three resulting from FP7 projects represent one third of the total.

Most of the projects agreed a PIP with the EMA-PDCO and the PIPs completion rate was slightly higher than the PIP completion percentage as a whole [16.6 vs. 12% (13)].

Moreover, although most projects did not fulfill the primary objective of obtaining a PUMA, other outcomes were achieved. These included successful completion of paediatric clinical trials, development of new patents and technologies, dissemination of results through scientific publications, updating of clinical guidelines, conducting EU-wide surveys on paediatric clinical practice and updating state-of-the-art in niche therapeutic subsets, such as neonatal-only diseases and paediatric pain, as evidenced by the analysis of FP7 project reports. Remarkably, despite all the challenges in implementing these projects and plans, results from our survey emphasised that, without this funding, obtaining a centralised marketing authorisation would not have been possible.

Despite the projects were not specifically aimed at performing drug repurposing, they offered a good insight on the main challenges encountered by stakeholders engaged in paediatric drug development plans for old medicines being repurposed for in-label use. Most of the plans were intended to extend the use of the active substances beyond the current use, including adding new indications not approved in adults, extending existing indications to paediatric subjects and developing new age-appropriate formulations or pharmaceutical forms. For one third of active substances in the sample, the indication studied in the FP7 project was completely new from the ones approved in adults. For example, metformin is currently approved Europe-wide for type-2 diabetes treatment, whereas the reference FP7 project intended to generate pharmacokinetics, efficacy and safety data on its use for polycystic ovary syndrome (PCOS) in children (14), thus bringing this indication within its approved label. Remarkably, the PIP agreed by PDCO for metformin study in PCOS was discontinued due to commercial reasons, as the sponsor deemed the commercial opportunity in Europe insufficient to justify the development efforts.²⁵ Similarly, the CloSed project intended to study clonidine for sedation in Paediatric Intensive Care Units generating evidence on its efficacy and safety, thus addressing an important paediatric therapeutic need. Unfortunately, the CloSed project did not complete its target due to financial difficulties of the sponsor, strict inclusion/exclusion criteria impacting on trial recruitment and long timelines for study approvals by ECs/CAs. In addition, within the DEEP project (15), the paediatric plan was successfully completed providing results supporting the extension of the use of deferiprone from thalassaemia major patients to children of all ages affected also by other rare hemoglobinopathies requiring chronic transfusions, such as the sickle cell disease. However, with only one recently authorised medicinal product in the EU²⁶ for children aged more than 12, there is still an unmet medical need for rare hemoglobinopathies in paediatrics.

Some of the aspects mentioned by the respondents to the survey were common to all paediatric drug development plans: first of all, the regulatory issues related to multiple interactions with the ECs/CAs, as largely reported (16–19), which have a significant impact on paediatric clinical research (20). This is often due to a jeopardised expertise on paediatric matters at the ECs/CAs level (16, 21, 22).

Also, recruitment challenges reported by the coordinators are quite well-known in the paediatric clinical research landscape (23, 24), affecting different therapeutic settings (25, 26) and representing one of the most common reasons for early trials discontinuation in paediatrics (27, 28). Another specific challenge mentioned by the respondents is to comply with requests received by EMA-PDCO, leading to the withdrawal of several PIPs before their agreement. Although the impulse that the Paediatric Regulation gave to paediatric clinical research in the European setting (29), a series of shortcomings of the current regulatory framework are highlighted in literature: clinical trials are insufficiently adapted to the paediatric clinical practice and start too late compared to adult trials (30), leading to an average delay of 8 years in the availability of paediatric medicines (16, 31), the methodology adopted in some PIPs is a transposition of the adult development plan (32), the enrolment rate does not reflect the number of paediatric patients potentially eligible (30); the complexity and number of proposed studies do not reflect the reality of paediatric clinical practice (33). Last but not least, until now the system has not promoted the development of new drugs for neonatal/paediatric indications only (34, 35). These considerations led to a substantial reform of the European regulatory and legislative framework started in 2022 and involving the Paediatric Regulation.²⁷ In fact, one of the new provisions introduced in this reform requires that medicinal products targeting a specific molecular pathway or possessing a mechanism of action linked to a different disease in adults (within the same therapeutic area) must also be studied in children.

However, some of the challenges we reported strictly reflect the poor attractiveness of repurposing off-patent medicines through the PUMA scheme,^28,29 despite its original intent to be a key element of the Paediatric Regulation. In fact, the number and type of studies required in a PIP for a PUMA, the populations to be recruited, the complexity of the administrative/technical procedures, are similar to those required for new/innovative paediatric products,³⁰ but running paediatric trials with off-patent medicines is affected by a higher degree of complexity (36). Consequently, developers prefer to apply under the simplified procedure outlined in the Directive 2001/83/EC for off-patent drugs rather than following the Paediatric Regulation route and discussing a PIP with the EMA-PDCO (35). Other common challenges reported by respondents and depending on the poor effectiveness of PUMA incentives refer to: the complexity of obtaining a modification to a product license, whether through a PUMA or otherwise, especially for non-commercial academic consortia; the economic value of medicines approved through a PUMA, as national health authorities responsible for pricing and reimbursement may limit revenues; and the small market size, due to the limited patient populations and the co-existence of generic competitors (13, 37, 38).

Specific attention must be paid to adequately support the efforts associated with the pharmaceutical development and manufacturing of new age-appropriate medicines formulations/strengths for old medicines. This is one of the main specificities of paediatric drug development and it has been cited as the stopping point for 3 FP7-funded projects. Indeed, the availability of cheaper options using extemporaneous galenic preparations might discourage developers from investing in new age-appropriate manufactured medicinal products, despite the challenges associated with extemporaneous preparations (39, 40). Notably, one of the primary reasons for trial failure in paediatric drug development is the absence of appropriate drug delivery systems (41). Medication palatability, swallowability and formulation are key elements of therapeutic drug-adherence and successful therapeutic outcome in paediatrics (42). Challenges in creating child-friendly formulations encompass clinical and technological aspects, including patient acceptance, the design of dosage forms, the selection of excipients, and the effects of dosage forms on pharmacokinetics and pharmacodynamics. Additionally, regulatory considerations, such as the limited size of the study population, as well as economic factors, and sustainability also play critical roles in the development process (42).

Based on these results, we can envisage that, despite research on novel medicines have an undoubtful relevance in addressing paediatric therapeutic needs, off-patent medicines being repurposed can still offer relevant treatment opportunities, also for rare neonatal diseases.

Thus, a series of support actions covering methodological and scientific aspects, as well as regulatory and legislative measures can make this process more effective. In this sense, several noteworthy initiatives on repurposing have been developed at EU and international level. The International Rare Diseases Research Consortium (IRDiRC)³¹ designed a guidebook to assist developers, including big pharma, clinicians, and patient-led initiatives, in repurposing existing drugs for new rare disease indications. A pilot call, jointly launched by Head of Medicines Agency/EMA in October 2021, provided free scientific advice at EMA/national level for not-profit-organisations and academia promoting repurposing development programmes.³² The aim of this initiative was to support, gather or generate sufficient evidence on the use of an established medicine in a new indication with the view to have this new use formally authorised by a regulatory authority. To date, several EU-funded networks are active on this topic. They include: REPO4EU,³³ that brings together 28 partners from 10 countries to find new uses for existing drugs, reducing development costs and time, and advancing personalised therapies;, REMEDi4ALL,³⁴ that is aimed at promoting patient-centric drug repurposing for rare and ultra-rare diseases, as well as other therapeutic areas; SIMPATHIC,³⁵ focused on accelerating drug repurposing for rare neurological, neurometabolic and neuromuscular disorders by exploiting similarities in clinical and molecular pathology.

Although their work and contribution are commendable, no dedicated focus for paediatric repurposing has been found (as an example, none of them address the issue of developing age-appropriate formulations).

On the other side, paediatric drug development remains one of the main focus areas of clinical research in Europe, also thanks to the intense work that collaborative initiatives are performing with an intense resources' investments. Some relevant examples include conect4children, that aims to generate a sustainable infrastructure that optimises the delivery of clinical trials in children; TEDDY European Network of Excellence for Paediatric Research and EPTRI³⁶ that are actively continuing their activities after the end of the funding period. Also, the paediatric clinical research consortia funded under the FP7-FRP represent a good example of public-private collaboration building their focus under a specific drug development plan and extending their activities also at the end of funding period. Last but not least, almost 40 paediatric specialty/multi-specialty, national/international networks are gathered under the umbrella of the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)³⁷ to support a broad range of activities, with the final aim of enhancing the development and availability of medicines for children across Europe.

Beyond the EU setting, at Food and Drugs Administration (FDA) level, the CURE-ID platform³⁸ was launched in 2019 for health care professionals to report novel uses of existing medicines. Initially, it was focused on difficult-to-treat infectious diseases (including COVID-19), but now it includes information also on rare cancers and rare genetic disorders.

As support action, it would be useful to have collaborations between existing paediatric and paediatric initiatives to establish specific pathways for paediatric drug repurposing, starting from a common and shared definition.

Additionally, another improvement in the effectiveness of off-patent paediatric drug development plans can come from the revision of the current EU pharmaceutical legislation, including the Paediatric Regulation. Despite the wide debate around the PUMA concept and incentives, they remained unchanged in the current proposed text of the new legislation, that is expected to be finalised by 2027 (1).^39,40 Thus, we do not expect any major impact on the number of PUMAs at EU level, also considering that the FP7 funding scheme has not been renewed as systematic support action, nor similar support actions are foreseen in the current legislation. Nevertheless, some positive effects can derive from the introduction of a more agile PIP system, the so called “initial PIP,” as many off-patent products currently registered in EU according to other regulatory tools (e.g., the Directive 2001/83/EC pathway) may be moved to PUMA if the PIP is simplified.

To our knowledge, this is the only in-depth analysis of the results of the FP7 funding to develop off-patent medicines, as derived from the obligation posed by the Paediatric Regulation. The qualified profile of respondents, as highlighted by their direct involvement in the projects, together with the high response rate, increases the value of the presented data. On the other hand, we acknowledge as a limitation that this work only analyses the effects of the funding scheme. Further insight into off-patent medicines developed according to the provisions of the Paediatric Regulation would be useful and could be pursued in the future.