1. Introduction
The development of paediatric medicines has been a long-term problem with many conditions needing treatment using medicines off-label due to lack of indications for paediatrics and appropriate formulations [
1]. According to the European Medicines Agency (EMA) definition, off-label use is the “use of a medicine for an unapproved indication or in an unapproved age group, dosage or route of administration” [
2]. Importantly, many paediatric patients will receive an off-label prescription during hospital stays. A survey, in the year 2000, of unlicensed and off-label use of medicines in European countries across five hospitals found that over half of paediatric patients received an off-label or unlicensed prescription [
3].
In 2004, the EMA stated that the evidence demonstrating the risks of using medicines off-label in paediatrics was sufficient to trigger changes to the legislation for paediatric drug development [
4]. Notably, paediatric patients receiving off-label therapies had a significantly higher risk of adverse drug reactions [
5] with over a third of off-label prescriptions resulting in an adverse event. These adverse events included fatalities and hospitalization [
4]. Because of the high percentage of paediatric patients receiving an off-label prescription, there is a large number of children at risk of these adverse events. Recently, an EAP/ESDPPP policy statement was published that provided an up-to-date review on the paediatric off-label medications used as well as a checklist for good practice comprising conditions that healthcare providers should consider when prescribing off-label medicines in paediatrics [
6].
On 26 January 2007 the European Union introduced the European Union Paediatric Regulation (EUPR), which aimed to yield more medicines for paediatric use and better information about medicines for paediatrics and to include more paediatric patients in clinical trials [
7] leading to a reduction in off-label use of medicines in this population [
8]. As part of the new legislation, paediatric investigation plans (PIPs) have to be submitted with every new marketing authorisation application (MAA) to outline what the sponsor will do to investigate their product within the paediatric population. According to the EMA [
7], “A PIP requirement also applies when a marketing-authorization holder wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorized and covered by intellectual property rights”. This brings a separation between relatively new and old drugs available as generics for which investment in those three new (indication, pharmaceutical form, route of administration) scenarios is less appealing to sponsors. For “older drugs”, an incentive known as paediatric use marketing authorization (PUMA) also requiring a PIP has been made available [
9].
Decisions to approve or decline PIPs are taken by the Paediatric Committee (PDCO) of the EMA and an outline for the application process can be seen in
Figure 1. The PDCO can take one of six decisions (
Table 1) when considering a PIP application, which are based on the pharmaceutical company’s specific request. A positive decision by the PDCO include those indicated with a P or PM abbreviation (
Table 1). Pharmaceutical companies who are granted positive decisions are expected to complete new research in paediatrics for their product as agreed in the plan. Implementation of these requirements have been met with controversy by some authors and stakeholders who point at the amount of resources consumed as well as suggesting that children may be exposed to potential harm through unnecessary studies for some products [
10,
11,
12].
In 2010, the EMA published a report [
15] on a survey about off-label and unlicensed use of medicines in Europe. This report was a legal requirement of the EUPR and was based on data gathered about medicine use in paediatrics from 22 countries in Europe. This report found that anti-arrhythmic, anti-hypertensive, proton pump inhibitors, H2 antagonists, anti-asthmatic, and anti-depressant drugs were the most common classes of medicines used off-label in paediatrics. These results highlighted the therapeutic areas lacking sufficient marketing authorizations (MAs) suitable for paediatric patients and, thus, involving frequent off-label use. Importantly, common classes of drugs used to treat cardiovascular diseases were reported among those with the greatest need for paediatric development.
In order to classify paediatric medicinal needs, the EMA produced three key documents (
Table 2.). The assessment of the paediatric needs (APN) list [
16] was prepared by the Paediatric Working Party and comprises 21 therapeutic areas. The other two documents, the off-patent priority list (OPPL) [
17] and the continuously updated inventory of paediatric medicines (IPM) [
18], build upon the original APN and add new active ingredients released since its publication. In addition, it has been shown [
19] that a gap exists between the therapeutic needs identified and the PIPs approved by the PDCO. In 2014, a study found that, of the 357 active substances on the APN list, only 14% had a positive PIP associated [
19]. This reveals the insufficient progress in paediatric drug development that addresses previously identified therapeutic needs, despite the EUPR making PIPs mandatory for all new MA applications.
Because several classes of cardiovascular diseases (CVD) medicines have been identified in the EMA report [
10] as being used commonly off-label, there is a need to investigate the current landscape of PIPs in this therapeutic area and its recent evolution. This research aimed to assess whether established paediatric CVD needs have been met by PIP applications or not.
2. Materials and Methods
2.1. Overall PIP Activity
To search for all available PIPs and filter them by decision type taken by the PDCO: “P”, “PM”, “RP”, “RPM”, “RW”, and “W” (
Table 1) the EMA drug search engine [
20] was used. The EMA drug search engine was preferred to other available search engines, because it contains the most up-to-date list of PIPs. In addition, it contains all the PIPs published since the legislation was enforced in 2007 and allowed the most accurate search of data needed for this research.
PIP decisions were filtered by year using 1 January to 31 December in the “date of opinion” search fields for each year. This ensured no overlap between years and enabled constructing a chronologic timeline for the data. The PIPs found were classified by decision type using the 6 decision types found in
Table 1. These classifications were used to aid analysis of the data. The last PIP information recorded for this dataset was acquired on the 20 October 2019, after which this research focused in other aspects (see
Section 2.2 and
Section 2.3). Thus, this work provides a perspective on the overall PIP activity registered over 12 years from 1 January 2007 to 20 October 2019.
2.2. PIP Activity in Specific Therapeutic Areas
To search for all available PIPs and classify them by the corresponding therapeutic area, the following steps were taken: The 21 therapeutic areas used by the EMA were used to ensure that no PIPs were missed during the data search. Each therapeutic area was searched using the corresponding filter in the “therapeutic area” search criteria [
20]. The PIPs found were further subdivided by decision type (
Table 1) as above.
Following this, the three key documents: APN, OPPL, and IPM (
Table 2) were scrutinized [
16,
17] The number of active substances corresponding to the same 21 therapeutic areas considered for the PIPs in each of the three documents was recorded. This enabled a direct comparison between the sets of results.
2.3. PIPs Addressing Paediatric Cardiovascular Needs
To assess whether established paediatric CVD needs have been met by PIP applications the following steps were taken. First, the results from the data search in the documents outlining the paediatric medicinal needs (see
Section 2.2 above) were used to calculate the total number of active substances in “cardiovascular diseases” that required further development. At this stage, the name of each active substance was recorded in a separate dataset, and duplicates across the three documents listed in
Table 2 were removed. Removing duplications enabled a better estimation of the number of active substances. By following these steps, the authors compiled the so-called “complete list of paediatric cardiovascular medicinal needs” (PCMN).
Next, using the EMA drug search engine [
20] each active substance on the PCMN list compiled by the authors was searched for filtering by name. The EMA repository contains all PIPs produced, so searching for each active substance enabled identification of any PIPs for a product containing the relevant active substance in a straightforward manner.
Further data mining was conducted using the same EMA drug search engine but using the filters “Paediatric Investigation Plan”, “P”, “PM” in “decision type”, and “Cardiovascular diseases” in the “therapeutic area” search fields. Since all procedural steps leading to a PIP decision are recorded and stored in the EMA repository, this strategy enabled quick access to any positive PIP decisions taken. Each positive PIP was scrutinized in detail, and the data from the fields “indication”, “completion date”, and “compliance check” were recorded.
A cross-check was made between the active substances on the PCMN list, and the set of products to treat cardiovascular needs with positive PIPs (a P or PM decision) recorded. This comparison focused on active substances and products that had indications for paediatric heart failure and/or hypertension. These results from this cross-check were used to establish whether the active substances requiring paediatric development had been targeted with PIP applications. For clarity, the PIPs regarding hypertension included both systemic hypertension and pulmonary arterial hypertension, and those PIPs corresponding to heart failure did not mention a specific type of heart failure (see
Supplementary Material S1-6 and S1-7).
To search for paediatric information in the summary of product characteristics (SmPCs) of CVD products with a positive PIP the following was done: The products identified previously with a positive PIP (a P or PM decision) in cardiovascular diseases (CVD) were searched by product name in the EMA repository. Where available, the summary of product characteristics (SmPC) published by the EMA for the product was scrutinized for information pertinent to paediatric patients. In particular, the information found in sections 4.2, 4.3, 4.4, 4.5, 4.8, 5.1, 5.2, and 5.3 of the product information was recorded in detail, as these are the sections where paediatric information is most commonly provided. For products without a label accessible through this repository because of the product was authorized before the EMA was established—or was not yet approved by EMA or had been approved through the national procedures—the Electronic Medicines Compendium (eMC) was searched [
21]. The search was done using the product and manufacturers name, and the summary of product characteristics (SmPC) was scrutinized for the same details as above.
2.4. Study Limitations
This work represents a snapshot of the PIP repository between 1 January 2007 and 20 October 2019, and no updates subsequent to this date were included in the analysis. To the authors’ knowledge, all relevant information from the EMA repository was gathered, but the manual data mining process precludes absolute certainty. The analysis shown is based in the data gathered, which are available in the supplementary files, but the authors chose the aspects in which this analysis focused. For transparency, we provide all the data gathered as supplementary information so other researchers can perform other analysis, test other hypothesis focusing on other aspects, and perhaps reach different conclusions to ours. Finally, all results and conclusions have been based exclusively on the publicly available information at the EMA repository, particularly that regarding PIPs. The authors acknowledge that this is but one of the many aspects involved in paediatric medicines development and that other aspects such as clinical trials activity and positioning by health technology assessment bodies and prescribers are also crucial components in this complex area.
5. Conclusions
Overall, this research showed that a positive trend in the development of paediatric medicines since the establishment of the EUPR. There is, however, an imbalance between the current therapeutic needs of the paediatric population and the number of PIPs agreed across the therapeutic areas. Whilst significant advances have been made in infectious diseases, oncology, and pneumology–allergology, CVD has lagged behind. This suggests that paediatric drug development usually follows the development pipelines for adult medicines and is driven by adult medical needs; a larger focus is needed on developing medicines for specific paediatric indications.
Since the EUPR was established, some gaps in paediatric CVD needs have not been addressed. Importantly, the lack of paediatric medicines to treat hypertension and heart failure demonstrates a lack of commitment to tackle this unmet need in children. In addition, the significant number of waivers granted in CVD suggest the paucity in medicines being developed to target specific paediatric conditions.
This research aimed to identify the gaps in the therapeutic area of paediatric CVD, providing evidence needed to support future developments. As illustrated by Diovan 3 mg/1 mL, future research can bring further medicines to treat CVD in paediatrics on-label where previously treatment with off-label products was the only alternative. Tackling paediatric needs requires a concerted effort by industry and regulators, but as this case study also demonstrates, without commitment from health care authorities and prescribers, it will be challenging to reduce off-label use of paediatric CVD medicines.