Article Text
Abstract
Introduction This paper focuses on the authorisation of new medicines, new indications and new pharmaceutical forms or strengths for use in children and also on the availability of paediatric information in the product information of centrally authorised medicinal products following the enforcement of the Paediatric Regulation on 26 January 2007.
Objectives To investigate whether the Paediatric Regulation has led to more medicines available for children in the European Union (EU) and if more information on paediatric use is now available in the product information of medicines authorised via the centralised procedure.
Materials and methods We retrospectively analysed the centrally authorised medicinal products in the EU that had an approval for an initial marketing authorisation, a type II variation, or a line extension during the years 2004–2006 and 2012–2014. Medicinal products not subjected to the obligations of the Paediatric Regulation were excluded.
Results In 2004–2006, 20 new medicines and 10 new indications were centrally authorised for paediatric use compared with 26 new medicines and 37 new indications in 2012–2014. The number of medicines with a new pharmaceutical form or strength for use in children was eight in 2004–2006 and seven in 2012–2014. There was a huge increase in the number of products with changes of paediatric relevance in the summary of product characteristics in 2012–2014 compared with 2004–2006.
Conclusions The entry into force of the Paediatric Regulation has had a positive impact on paediatric drug development with more medicines available for children in the EU and substantially more information available for clinicians on paediatric use in the product information.
- general paediatrics
- paediatric practice
- therapeutics
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What is already known on this topic?
Drug development is primarily driven by adult development as the Paediatric Regulation links the adult indication to the paediatric investigation plan.
There is extensive off-label use of medicines in the paediatric population which increases the risk of adverse drug reactions.
The Regulation aims to stimulate research into the uses of medicines in children and to lead to their authorisation in all age groups.
What this study adds?
The entry into force of the Regulation has had a positive impact on paediatric drug development.
More medicines are available for children in the EU and substantially more information is available for clinicians on paediatric use in the product information.
The increased number of medicines and the improvement of product information increase the probability of a decline in off-label use of medicines.
Introduction
The Paediatric Regulation (EC No 1901/2006, from here on referred to as the Regulation) came into force in the European Union (EU) on 26 January 2007.1 The three key objectives of the Regulation are (1) to facilitate the development and accessibility of medicines for use in children (from birth to less than 18 years old), (2) to ensure that these medicines are ethically researched and are authorised appropriately and (3) to improve the information available on the use of medicines in children.2
The Regulation led to the establishment of the Paediatric Committee (PDCO), which is responsible for the scientific assessment and agreement of paediatric investigation plans (PIPs). A PIP is a research and development plan aimed at ensuring that the necessary data are obtained through studies in children to support the authorisation of a medicine for children. All applications for marketing authorisation for new medicines—excluding generic, hybrid, biosimilar, well-established use, herbal and homeopathic applications—have to include the results of studies as described in an agreed PIP. The PDCO may grant waivers when development of a medicine in children is not needed or not appropriate or grant deferrals when it is appropriate to conduct studies in adults prior to initiating studies in the paediatric population or when studies in the paediatric population will take longer to conduct than studies in adults (Article 7).1 Marketing authorisation applicants are required to include in their PIP any measures to adapt the formulation of the medicinal product to be age appropriate in different subsets of the paediatric population. The requirements of the Regulation also apply when a marketing authorisation holder wants to add a new indication (variation) or a new pharmaceutical form or route of administration (line extension) for a medicine that is already authorised and covered by intellectual property rights (Article 8).1
This paper focuses on the authorisation of new medicines, new indications and new pharmaceutical forms or strengths for use in children and also on the availability of paediatric information, that is, changes to the product information (Summary of Product Characteristics (SmPC)) of centrally authorised medicinal products following the enforcement of the Regulation in the EU. In addition to changes as a result of studies included in a PIP opinion, changes to the SmPC can also result from paediatric study results (Article 45/46) and non-clinical or pharmacovigilance study results.3 Article 45/46 requires marketing authorisation holders for medicines authorised in the EU to submit information on all paediatric studies completed by the date of entry into force of the Regulation on 26 January 2007 (Article 45) and studies completed since this date (Article 46).1
In June 2013, the European Commission (EC) published a report on the first 5 years of the Regulation2 followed by a 10-year report on implementation of the Paediatric Regulation published in October 2017.4 The EC reports took into account the two reports prepared by the European Medicines Agency (EMA) with its Paediatric Committee.3 5 The EMA concluded that the Regulation has resulted in an increased number of better and more available medicines for children and also more information available on paediatric use. From 2007 until 2016, 267 new medicines for use in children and 43 new pharmaceutical forms appropriate for children were authorised in the EU.5
The aim of this analysis, conducted in 2015, was to investigate whether the Regulation has led to more medicines available for children in the EU and if more information on paediatric use is now available in the SmPC of medicines authorised via the centralised procedure. This was done by comparing data collected from 3 years immediately before the Regulation came into force (2004–2006) with the last three most recent years at the time of the analysis (2012–2014). The latter reference period was selected in order to analyse a potential impact of the Regulation, which was not expected to be seen immediately after entry into force as medicine development is a lengthy process.
Materials and methods
The EMA product information and application tracking system (SIAMED) was searched to identify all centrally authorised medicinal products in the EU that had an approval for an initial marketing authorisation, a type II variation, or a line extension (type I variations were excluded) during the years 2004–2006 and 2012–2014.
For the initial marketing authorisations, we retrospectively analysed the first approved SmPCs and the EMA Assessment Reports available in the EMA Document Records Electronic Archive Management database (DREAM). The following information was extracted: new paediatric indications and other paediatric information in the SmPC sections. By searching the EMA Paediatric Record Application database (PedRA) and the EMA website, we checked if the products had an agreed PIP in place, that is, linked to the requirements of the Regulation.
For the changes to already authorised medicinal products, that is, type II variations (major changes to a marketing authorisation) and line extensions (changes to the active substance, available strengths, pharmaceutical forms or the route of administration), we searched the SmPCs and the EMA Assessment Reports that were linked to the corresponding application number. The following information was extracted: new paediatric indications (SmPC section 4.1), new information on paediatric posology and method of administration (SmPC section 4.2) and other new paediatric information (SmPC sections 4.3–5.3). We also checked if the initial marketing authorisations, type II variations and line extensions in years 2012–2014 met the conditions of Article 7 or Article 8 of the Regulation and had an agreed PIP in place.
Results
There was a total of 1514 centrally authorised medicinal products with approved initial marketing authorisations, type II variations and line extensions in the years 2004–2006 and 2012–2014: 674 medicinal products for the years 2004–2006 (207 in 2004, 221 in 2005 and 246 in 2006) and 840 medicinal products for the years 2012–2014 (315 in 2012, 259 in 2013 and 266 in 2014). We excluded from the analysis medicinal products that are not subjected to the obligations of the Regulation, that is, generic, hybrid, biosimilar, homoeopathic and traditional herbal medicinal products and products being assessed under the well-established use legal basis. The remaining 571 medicinal products for the years 2004–2006 (174 in 2004, 193 in 2005 and 204 in 2006) and 713 medicinal products for the years 2012–2014 (263 in 2012, 221 in 2013 and 229 in 2014) were all checked for new paediatric information in their SmPCs and EMA Assessment Reports.
The results from the investigated SmPCs and EMA Assessment reports are summarised in table 1 and figures 1 and 2. Detailed information regarding the medicinal products with new paediatric indications (eg, age ranges), new pharmaceutical forms or strengths and other changes of paediatric relevance in the SmPCs can be found in the online Supplementary annex. For the years 2004–2006, 20 new medicinal products (initial marketing authorisations) and 10 new indications (type II variations) were centrally authorised for paediatric use. For the years 2012–2014, the number increased to 26 new medicinal products and 37 new indications centrally authorised for paediatric use of which 45 (71%) met the conditions of Article 7 or Article 8 of the Regulation, that is, had an agreed PIP in place (see online Supplementary annex). Eighteen medicinal products (14 new products and four products with new indications centrally authorised for paediatric use) did not fall under the obligations of either Article 7 or Article 8 and were therefore not linked to the requirements of the Regulation. As seen in figure 1, the proportion of new medicinal products and new indications centrally authorised for use in children in relation to the number of all other centrally authorised new medicinal products (initial marketing authorisations) and new indications (type II variations extension of indication) has increased from 14% in 2004–2006 to 25% in 2012–2014. The number of medicinal products with a new pharmaceutical form or strength (line extensions) for use in children has decreased slightly from eight products in years 2004–2006 to seven products in years 2012–2014. All these seven products had an agreed PIP in place.
Supplementary file 1
New medicinal products for children and therapeutic areas
All new medicinal products (initial marketing authorisations), new indications (type II variations) and new pharmaceutical forms or strengths (line extensions) centrally authorised for paediatric use in years 2004–2006 and 2012–2014 were classified according to their therapeutic areas based on each substance’s Anatomical Therapeutic Chemical (ATC) code (figure 3). Of all therapeutic areas, medicines used to treat or prevent infectious diseases (anti-infectives for systemic use, e.g. vaccines, antivirals, antibiotics, antimycotics) accounted for the highest proportion both in years 2004–2006 (50%; n=19) and in years 2012–2014 (45%; n=31). There was an increase both in the number and in the proportion of medicines in the antineoplastic and immunomodulation agents group (e.g. immunosuppressants, immunostimulants, antimetabolites) in 2012–2014 (20%; n=14) compared with 2004–2006 (13%; n=5). Also, medicines used to treat diseases of the blood and blood-forming organs (blood coagulation factors or other antithrombotic agents) increased from two (5%) in 2004–2006 to six (8%) in 2012–2014.
Other changes of paediatric relevance
We analysed the type II variations and line extensions for centrally authorised medicinal products in years 2004–2006 and 2012–2014 resulting in a change of any paediatric relevance in the SmPC sections 4.2–5.3, that is, all sections except 4.1 (indications) (figure 4 and table 2). This analysis also included medicines that did not necessarily have a paediatric indication. Each centrally authorised medicinal product could have changes to several sections in the SmPC. These changes to the SmPC can be a result of completed studies included in a PDCO opinion on a PIP, paediatric study results (Article 45 and 46 assessment recommendation) or non-clinical or pharmacovigilance study results. As seen in figure 4, there has been a huge increase in the number of products with one or more changes of paediatric relevance in the SmPCs in 2012–2014 compared with the years 2004–2006, especially in sections 4.2, 4.4, 4.8, 5.1 and 5.2. Changes to SmPC section 4.2 include new paediatric dosing recommendations, new clarified paediatric dosing information and also added information that the product is not recommended for use in children or in specific age groups of children. In years 2004–2006, 32 products had changes of paediatric relevance to this section. Of these, about 80% had new or clarified paediatric dosing recommendations and about 20% had a new statement clarifying that use is not recommended. In years 2012–2014, out of 109 products with changes of paediatric relevance to SmPC section 4.2, about 60% had new or clarified paediatric dosing recommendations and 40% specified that use in children or in specific age groups of children is not recommended.
Discussion
This comparison of two 3-year periods shows, in accordance with the EMA 10-year report,5 that since the entry into force of the Regulation in 2007, there are more medicines available for children in the EU. If the total number of authorised products has increased between the two time periods, one would expect the number of those authorised for children to increase similarly and this may not be an effect of the Regulation. Interestingly, both the absolute number and the proportion of paediatric initial marketing authorisations and type II variations for new paediatric indications have increased in years 2012–2014 compared with years 2004–2006 (figure 1), indicating an effect of the Regulation. On the contrary, in our analysis, no improvement was seen in the number of medicinal products with a new pharmaceutical form or strength for use in children when comparing the two time periods.
Paediatric drug development is primarily driven by adult drug development as the Regulation links the adult indication to the obligation for a paediatric investigation plan. This is demonstrated by the fact that most authorisations were seen in the area of infections (figure 3) due to the extensive research and development of antiviral agents in the recent years.
In addition to new paediatric products and indications, there has also been an improvement in availability of paediatric information for prescribers as there is substantially more information on paediatric use in the SmPCs of authorised medicinal products after 2007, especially with regard to new information on paediatric posology, safety, warnings, clinical trial data and paediatric pharmacokinetics and pharmacodynamics. The percentage of products with a new statement in SmPC section 4.2 clarifying that the product is not recommended for use in children due to no or insufficient data has increased in years 2012–2014 compared with years 2004–2006. In most cases, this statement is included when a deferral has been granted, and the whole body of data from the PIP will only become available at a later stage, after completion of the PIP. Even if a medicine is not authorised for use in children, inclusion of such information in the SmPC could assist prescribers in making decisions on the use of a medicine.
Limiting off-label use, which is extensive due to the relatively small number of available medicines that have been studied and authorised for use in the paediatric population, is one of the objectives of the Regulation. Off-label use is associated with an increased risk of adverse drug reactions and other drug-related problems.6 The increase in both the number of medicines available to children and the improvement of product information available to clinicians following the entry into force of the Regulation is expected to result in a decline in the off-label use of medicines. However, increased information in the SmPC does not per se reduce off-label use of medicinal products. This is due to several reasons, including insufficient knowledge among prescribers, gradual adaptation to revised medical treatment recommendations and lack of approved treatment options. It has to be also considered that while Paediatric Investigation Plans are being conducted, information on pharmacokinetic or pharmacodynamic data in children may become available (and thus included in the product information) well before completion of formal efficacy studies in the paediatric population. It is nevertheless considered useful to include all available information in the SmPC, so that prescribers may have the most up-to-date knowledge when deciding between different therapeutic alternatives.
Other recently published studies investigating the impact of the Regulation show that the implementation of the Regulation has ensured and facilitated the development of new and better medicines for children.7 8 However, there have only been a few new studies on paediatric use for already authorised off-patent medicines8 and orphan drugs9 and there is still a need to continue assessing data from paediatric studies conducted before the implementation of the Regulation (Article 45).7
Our study has some limitations. Showing differences between two periods in time does not per se establish causality. We chose to analyse two different time periods, the last 3 years before the Regulation entered into force (2004–2006) and the last 3 years after, for which we had complete data (2012–2014). However, due to the considerable time needed for paediatric development, it is possible that a later 3-year period could have shown even more marked differences.
Conclusions
The results of this study demonstrated that the entry into force of the Paediatric Regulation in 2007 has had a positive impact on paediatric drug development with more medicines available for children in the EU and substantially more information available for clinicians on paediatric use in the SmPCs of authorised medicinal products. Solutions should be explored to optimise the positive impact from the Regulation so medicines are developed to cover unmet paediatric needs which are often not entirely linked to adult needs or the most profitable areas which drive pharmaceutical development.
Footnotes
Contributors SN and CP were responsible for the design of the work and data collection. SN was responsible for data analysis and interpretation and PT and CP critically reviewed the results. All authors contributed to writing the article (drafting of the article by SN and critical review and revision by PT and CP). All authors gave their final approval of the version to be published.
Disclaimer The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the European Medicines Agency, Karolinska Institutet or the Karolinska University Hospital.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.