New regulatory requirements in the pharmaceutical sector

By Mauro Turrini



Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use (hereinafter, “the Paediatric Regulation”) is intended to tackle the problems resulting from the absence of suitably adapted medicinal products for the paediatric population (including inadequate dosage information, non-availability to the paediatric population of therapeutic advances, suitable formulations and routes of administration as well as use of magistral or officinal formulations to treat the paediatric population).

In particular, the Paediatric Regulation introduces the requirement to include information about paediatric studies in the Marketing Authorisation (MA) application. This requirement, already mandatory for new medicinal products as from 26th of July 2008, will start soon to be compulsory also for previously authorised medicinal products covered by a supplementary protection certificate (SPC) or a patent, which qualifies for the granting of the SPC (as from 26 January 2009).

According to Articles 7 and 8 of the Paediatric Regulation, all applications for a new MA, as well as all applications for variation and/or line extension of medicinal products covered by a SPC or a patent (which qualifies for the granting of the SPC), submitted, respectively, after the 26 July 2008 and 26 January 2009, will be regarded as valid only if they include, in addition to the particulars and documents already 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). This obligation does not apply in cases where the Applicant can provide a decision issued by the EMEA granting a: i) product-specific waiver; ii) class waiver or; iii) deferral1.

To compensate the new requirement above, Title V of the Paediatric Regulation provides for a number of rewards for the Applicants.

In this regard, Article 36 of the Paediatric Regulation provides that, for applications under Articles 7 or 8, which include the results of all studies conducted in compliance with an agreed PIP, the holder of the patent or SPC shall be entitled to a six-month extension of the period referred to in Articles 13(1) and 13(2) of Regulation (EEC) No 1768/92. Such a reward also applies in those cases where completion of the agreed PIP failed to lead to the authorisation of a paediatric indication, but “the results of the studies conducted are reflected in the summary of product characteristics and, if appropriate, in the package leaflet of the medicinal product concerned”.

This 6 month extension reward however will not apply in cases where:

  • the centralised, mutual recognition, decentralised (and purely national) procedures have been used and the product has not been authorised in all Member States;

  • the product, although protected by an SPC or under a patent which qualifies for the granting of the SPC, is designated as orphan medicinal product pursuant to Regulation (EC) No 141/2000;

  • the product, following an application under Article 8 of the Paediatric Regulation, obtained a one-year extension of the period of marketing protection for the new paediatric indication2.

Moreover, additional rewards are provided in cases of orphan medicinal products as well as Paediatric Use Marketing Authorisations (PUMA). In particular:

  • In relation to orphan medicinal products, Article 37 of the Paediatric Regulation provides that in case of successful applications including the results of all studies conducted in compliance with an agreed PIP, the ten-year period of data exclusivity (i.e. see Article 8(1) of Regulation (EC) No 141/2000) shall be extended to twelve years;

  • In relation to PUMAs, Article 38 of the Paediatric Regulation provides that in cases where a PUMA is granted (irrespective of the registration procedure followed), the data and marketing protection exclusivity periods provided by EU legislation shall apply3.

Finally, we refer to guidance recently provided by the EMEA which, in order to ensure compliance with the new requirement provided by the legislation, has published on its website a procedural advice document describing the procedures for the operation of: i) validation of MA applications and extension/variation applications; and ii) the compliance check with an agreed PIP.

For further information, please refer to

Advanced therapies

On 10 December 2007, Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products (the ATMP Regulation) and amending Directive 2001/83/EC and Regulation (EC) 726/2004 was published in the Official Journal of the European Union. The ATMP Regulation intends to define and regulate existing and future ATMPs, such as gene therapy, somatic cell therapy and tissue engineered products, intended for the market in Member States, being either prepared industrially or manufactured by a method involving an industrial process.

In particular, the ATMP Regulation, which entered into force on 30 December 2007 and will apply from 30 December 2008, provides for several new requirements and incentives for industries developing ATMPs. In particular, the ATMP Regulation provides for:

  • specific rules on the authorisation, supervision and pharmacovigilance of ATMPs (i.e. revised technical requirements as to SPC, labelling and package leaflet; new additional post-authorisation requirements as to the follow-up of efficacy/adverse reactions, risk management and traceability);

  • an EMEA final evaluation in the case of combined ATMPs; and

  • special incentives for Small and Medium Enterprises (SMEs) developing ATMPs (i.e. Scientific Advice on the design and conduct of pharmacovigilance and risk management4; ii. Scientific Recommendation on ATMP classification5; iii. Certification of quality and non-clinical data6; iv. Additional fee reduction for SMEs or hospitals are also available (only during the transitional period referred to in Article 29), provided they can prove there is a particular public health interest in the Community7.

Notably, manufacturers, companies and hospitals which already have ATMPs on the market (i.e. ATMPs placed on the EU market according with national or EU legislation of 30 December 2008) will also need to comply with the new requirements. In this regard, an application in compliance with Annex I to Directive 2001/83/EC, as amended, and with the Paediatric Regulation will have to be submitted to the EMEA for evaluation (unless the exemption under Article 28(2) of ATMP Regulation applies8) by 30 December 2011 (for ATMP other than tissue engineered products) and 30 December 2012 (for tissue engineered products) - the so-called transitional period. The review process will then follow the normal procedure for the centralised procedure for ATMPs9.

It should be noted, however, that the above mentioned deadlines should be considered as already including the time needed for evaluation (i.e. up to a maximum of 210 days’ active review time) and authorisation. Therefore, concerned manufacturers, companies and hospitals should seek regulatory advice as soon as possible in order to discuss the data package to be submitted for this procedure10.

Finally, it should be noted that as provided in the ATMP Regulation and as part of the Implementation plan agreed between the European Commission and the EMEA, the following documents will be issued in the near future:

  • by the EC Commission: i) GCP guidelines (Article 4); ii) GMP guidelines (Article 5); iii) Amend Annex I to Directive 2001/83/EC (Article 7); iv) Traceability guidelines (Article 15(7)); v) Implementing provisions on certification of quality/non-clinical data (Article 18); vi) Appoint CAT patients/clinicians representatives (Article 21(c)(d)).

  • by the EMEA: i) Specific procedures for the evaluation of ATMP (Article 8); ii) Guidelines on Post-authorisation follow up/Risk management (Article 14); iii) Establishment of CAT (Articles 20 and 21); iv) CAT’s Rules of Procedure (Article 61(8) Regulation (EC) No 726/2004).

1 As to the rationale for these exclusions, please see Recital 4 of the Regulation, according to which the objectives pursued by the Regulation should be achieved without subjecting
the paediatric population to unnecessary clinical trials (i.e. waivers) and without delaying the authorisation of medicinal products for other age populations (deferral).
2 See Article 14(11) of Regulation (EC) No 726/2004 or Article 10(1), fourth subparagraph, of Directive 2001/83/EC (“significant clinical benefit in comparison with existing therapies”).
3 See Article 14(11) of Regulation (EC) 726/2004 as well as Article 10(1) of Directive 2001/83/EC.
4 90% fee reduction for SMEs and 65% for others (see Article 16 of ATMP Regulation).
5 See Article 17 of ATMP Regulation.
6 See Article 18 of ATMP Regulation, where for the first time a system of evaluation and certification of ATMP quality and, where available, non-clinical safety data is introduced in EU legislation providing a very useful tool for all EU SMEs. The system intends to incentivise the conduct of those studies and aims, in particular, to facilitate the evaluation of any future application for clinical trials and MA applications based on the same data.
7 50% reduction on MA fees and 50% for post-authorisation activities during 1 year (see article 19 of ATMP Regulation).
8 In line with Regulation (EC) 1394/2007. Please note that for this MA procedure, no fee will need to be paid to the EMEA.
9 ATMP prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility
of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient.
10 In particular, please note that for Module 5 of the (e)CTD, the data to be submitted can include information obtained from use of the product (surveillance data), but this might not
replace the requirement for controlled clinical trials.