5. Special cases in marketing authorisations: Paediatric medicines

1. Paediatric medicines

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There is broad consensus that children deserve access to medicines that have been specifically developed and researched for their use in young patients. However, for considerable time the development and testing of paediatric medicines      has historically been unsatisfactory.

Reasons for the absence of suitable medicines for the paediatric population included:

• inadequate dosage information (many medicines used in children were prescribed and administered based on physicians’ own experience rather than on the results of clinical research*)
• absence of suitable formulations and routes of administration (paediatricians had to adapt the dosage and form of medicines authorised for adults, for example, by using only a portion of a tablet for adults after dissolving*)
• ethical concerns about clinical research in children
• economic considerations hindering proactive investment in this sector (for example, the needs and biological and physiological characteristics of neonates are very different compared to teenagers, therefore additional age-appropriate research is required, increasing the complexity, time and cost of developing paediatric medicines).
• non-availability of therapeutic advances for the paediatric population,
• high variability or missing normative physiological data for different paediatric subgroups up to young adults on which to base the development of medicines

* These can be considered off-label use of adult medicines in children. This carries the risk of either lack of effectiveness or poses safety problems in children, the latter perhaps of lesser concern in adults but possibly important and serious in children. A 2017 study on off-label use of medicines in the EU suggested that in children 0-18 years of age the prevalence of off-label use was still widespread.

Regulation (EC) No 1901/2006/EC, the Paediatric Regulation, came into force in the European Union (EU) on 26 January 2007. It was seen as a response to the absence of sufficient numbers of suitable, authorised medicines for children. The regulation was adopted to “ensure that medicines are regularly researched, developed and authorised to meet the therapeutic needs of children”. Its objectives were to:

• facilitate the development and availability of medicines for children aged 0 to17 years of age;
• ensure that medicines for the treatment of children are subject to ethical research of high quality and are appropriately authorised for use in the paediatric population;
• improve the available information on the use of medicines in various paediatric populations.
• achieve this without unnecessary trials in children or delaying the authorisation of medicines for adults

It applies to both, “nationally” (MRP, DCP, national) as well as to centrally authorised medicines.

1.1. The Regulation – obligations and measures

• establishment of the EMA’s expert Paediatric Committee (PDCO) responsible for coordinating the EMA's work on medicines for children and to provide opinions on the development of paediatric medicines;
• a mandatory Paediatric Investigation Plan (PIP) (Artl. 7 and 8 of the Paediatric Regulation):
• binding research and development plan that details quality, non-clinical and clinical steps necessary for obtaining a paediatric indication, agreed with the Paediatric Committee (PDCO) at end of phase I studies in adults.
• Applications will be regarded as valid only if they include, in addition to the particulars and documents required by previous pharmaceutical legislation, the results of all studies performed and details of all information collected in compliance with an agreed Paediatric Investigation Plan (PIP) unless exempt because of a waiver.
• a system of PIP waivers for specific medicines or classes of medicines
• a system of PIP deferrals allows delayed development of the paediatric medicine
• the Paediatric Use Marketing Authorisation (PUMA): a new type of MA, a voluntary procedure, applicable to any off-patent medicine developed for exclusive use in the paediatric population.

1.2. The PDCO

The Regulation’s main impact was the establishment of the Paediatric Committee (PDCO).

The PDCO's main task:

• to assess and accept or amend the content of paediatric investigation plans (PIPs), which determine the studies that companies must carry out in children when developing a medicine. This includes assessing applications for a full or partial waiver and for deferrals.

The committee's other tasks in relation to paediatric medicines include:

• assessing data generated in accordance with agreed PIPs;
• adopting opinions on the quality, safety or efficacy of a paediatric medicine, at the request of the CHMP or a regulatory authority in a European Union (EU) Member State (MS);
• advising MSs on the content and format of data to be collected through surveys on the uses of paediatric medicines;
• advising and supporting the development of the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) of existing national European and extra EU networks, investigators and trial centres with specific expertise in the performance of studies in the paediatric population; Patient representatives are involved in the work of Enpr-EMA

• providing advice on questions on paediatric medicines, at the request of the EMA's Executive Director or the EC;
• establishing and regularly updating an inventory of paediatric medicine needs, in particular with a view to identifying research priorities
• advising the EMA and the EC on how to communicate the arrangements available for conducting research into paediatric medicines.

The PDCO is not responsible for marketing authorisation applications for paediatric medicines, which is in the remit of the CHMP.

1.3. Incentives and rewards

Apply if:

- development is compliant with agreed PIP (compliance statement in MA);

- results of studies (positive or negative) are included in the Summary of product Characteristics (SmPC) + Package Leaflet (PL);

- product is authorised in all Member States (except for PUMA)

They entail:

• for PUMA: 8 plus 2 years of data and market protection (compliance with agreed PIP necessary, irrespective of the MA procedure) and fee reduction for MA/post-authorisation activities
• for new medicines (article 7) or authorised medicines on-patent (article 8): a six-months extension to the supplementary protection certificate (SPC)^[1], i.e., a six-months patent extension*
  *no reward if the product, following an application under Article 8, obtained a one-year extension of the period of marketing protection for the new paediatric indication
• for paediatric orphan medicines: an additional two-years market exclusivity, added to the ten-years awarded under the Orphan Regulation.
• Scientific advice: prior to the submission of a PIP and during its implementation, free of charge for questions relating to the development of paediatric medicines as well as to the design and conduct of pharmacovigilance and risk management systems

Product-specific or class waiver or inconclusive studies in PIP do NOT trigger the reward.

1.4. Waivers and Deferrals

Waivers and deferrals apply to any new or in patent drug for which a MA or a MA variation is applied for (articles 7 and 8 of the Paediatric Regulation),

Waivers for specific medicines or classes of medicines:

• grant exemption to produce results from measures/studies in one or more paediatric subsets, for a given condition.
• do not prohibit performance of (paediatric) studies;
• allow rewards only if some measures have been completed, in compliance with a PIP

Can be given:

• for medicines that are likely to be ineffective or unsafe in part or all of the paediatric population;
• for medicines that do not represent a significant therapeutic benefit over existing treatments for paediatric patients
• when development of a paediatric medicine is not needed or is not appropriate, such as for diseases that only affect adults;

Deferrals:

• help avoid delaying marketing authorisation in adults, i.e. a MAA for adults is possible before completion of one or more studies/measures in the PIP;
• does NOT mean that a PIP application can be submitted late (e.g. after completion of adult development) but that the agreed measures in the PIP can be initiated and/or completed later in relation to the adult development.
• may be applicable to some or all measures in a PIP;
• are granted when adult study results are deemed necessary prior to initiating studies in children or when paediatric studies will take longer to conduct than studies in adults;
• even when studies are deferred, the PIP will include details of the paediatric studies and their timelines

1.5. Exemptions

The Paediatric Regulation allows exceptions to articles 7 and 8, such that a PIP or waiver is NOT required in case of:

• “Off-patent” medicines authorised in the EU (authorised products that do not have a valid Supplementary Protection Certificate (SPC) or a valid patent that qualifies for it.). A voluntary PIP is possible.
• New medicines belonging to some specific groups (Artl. 10 and 16 of Directive 2001/83):
  • Traditional herbal medicinal products
  • Homeopathic products
  • Generic products
  • Hybrid products (a PIP can optionally be agreed for future PUMA application)
  • Biosimilar products
  • Well-established medicinal use
• a class-waiver exists for a class of products in a condition

In all these cases, the necessity for paediatric studies is determined case-by-case under the responsibility of the CHMP.

Legal basis:

Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use;
Regulation (EC) No 1902/2006, and amending regulation in which changes to the original text were introduced relating to decision procedures for the European Commission.
Directive 2001/83 where applicable