(1)

New scientific progress in cellular and molecular biotechnology has led to the development of advanced therapies, such as gene therapy, somatic cell therapy, and tissue engineering. This nascent field of biomedicine offers new opportunities for the treatment of diseases and dysfunctions of the human body.

(2)

Insofar as advanced therapy products are presented as having properties for treating or preventing diseases in human beings, or that they may be used in or administered to human beings with a view to restoring, correcting or modifying physiological functions by exerting principally a pharmacological, immunological or metabolic action, they are biological medicinal products within the meaning of Annex I to Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (3), read in conjunction with the definition of medicinal products in Article 1(2) thereof. Thus, the essential aim of any rules governing their production, distribution and use must be to safeguard public health.

(3)

For reasons of clarity, complex therapeutic products require precise legal definitions. Gene therapy medicinal products and somatic cell therapy medicinal products have been defined in Annex I to Directive 2001/83/EC, but a legal definition of tissue engineered products remains to be laid down. When products are based on viable cells or tissues, the pharmacological, immunological or metabolic action should be considered as the principal mode of action. It should also be clarified that products which do not meet the definition of a medicinal product, such as products made exclusively of non-viable materials which act primarily by physical means, cannot by definition be advanced therapy medicinal products.

(4)

According to Directive 2001/83/EC and the Medical Device Directives the basis for deciding which regulatory regime is applicable to combinations of medicinal products and medical devices is the principal mode of action of the combination product. However, the complexity of combined advanced therapy medicinal products containing viable cells or tissues requires a specific approach. For these products, whatever the role of the medical device, the pharmacological, immunological or metabolic action of these cells or tissues should be considered to be the principal mode of action of the combination product. Such combination products should always be regulated under this Regulation.

(5)

Because of the novelty, complexity and technical specificity of advanced therapy medicinal products, specially tailored and harmonised rules are needed to ensure the free movement of those products within the Community, and the effective operation of the internal market in the biotechnology sector.

(6)

This Regulation is a lex specialis, which introduces additional provisions to those laid down in Directive 2001/83/EC. The scope of this Regulation should be to regulate advanced therapy medicinal products which are intended to be placed on the market in Member States and either prepared industrially or manufactured by a method involving an industrial process, in accordance with the general scope of the Community pharmaceutical legislation laid down in Title II of Directive 2001/83/EC. Advanced therapy medicinal products which are 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, should be excluded from the scope of this Regulation whilst at the same time ensuring that relevant Community rules related to quality and safety are not undermined.

(7)

The regulation of advanced therapy medicinal products at Community level should not interfere with decisions made by Member States on whether to allow the use of any specific type of human cells, such as embryonic stem cells, or animal cells. It should also not affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products containing, consisting of or derived from these cells.

(8)

This Regulation respects the fundamental rights and observes the principles reflected in the Charter of Fundamental Rights of the European Union and also takes into account the Council of Europe Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine.

(9)

All other modern biotechnology medicinal products currently regulated at Community level are already subject to a centralised authorisation procedure, involving a single scientific evaluation of the quality, safety and efficacy of the product, which is carried out to the highest possible standard by the European Medicines Agency as established by Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use (4) (hereinafter referred to as the Agency). This procedure should also be compulsory for advanced therapy medicinal products in order to overcome the scarcity of expertise in the Community, ensure a high level of scientific evaluation of these medicinal products in the Community, preserve the confidence of patients and medical professions in the evaluation and facilitate Community market access for these innovative technologies.

(10)

The evaluation of advanced therapy medicinal products often requires very specific expertise, which goes beyond the traditional pharmaceutical field and covers areas bordering on other sectors such as biotechnology and medical devices. For this reason, it is appropriate to create, within the Agency, a Committee for Advanced Therapies, which should be responsible for preparing a draft opinion on the quality, safety and efficacy of each advanced therapy medicinal product for final approval by the Agency’s Committee for Medicinal Products for Human Use. In addition, the Committee for Advanced Therapies should be consulted for the evaluation of any other medicinal product which requires specific expertise falling within its area of competence.

(11)

The Committee for Advanced Therapies should gather the best available expertise on advanced therapy medicinal products in the Community. The composition of the Committee for Advanced Therapies should ensure appropriate coverage of the scientific areas relevant to advanced therapies, including gene therapy, cell therapy, tissue engineering, medical devices, pharmacovigilance and ethics. Patient associations and clinicians with scientific experience of advanced therapy medicinal products should also be represented.

(12)

To ensure scientific consistency and the efficiency of the system, the Agency should ensure the coordination between the Committee for Advanced Therapies and its other Committees, advisory groups and working parties, notably the Committee for Medicinal Products for Human Use, the Committee on Orphan Medicinal Products, and the Scientific Advice Working Party.

(13)

Advanced therapy medicinal products should be subject to the same regulatory principles as other types of biotechnology medicinal products. However, technical requirements, in particular the type and amount of quality, pre-clinical and clinical data necessary to demonstrate the quality, safety and efficacy of the product, may be highly specific. While those requirements are already laid down in Annex I to Directive 2001/83/EC for gene therapy medicinal products and somatic cell therapy medicinal products, they need to be established for tissue engineered products. This should be done through a procedure that provides for sufficient flexibility, so as to easily accommodate the rapid evolution of science and technology.

(14)

Directive 2004/23/EC of the European Parliament and of the Council (5) sets standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. This Regulation should not derogate from the basic principles laid down in Directive 2004/23/EC, but should supplement them with additional requirements, where appropriate. Where an advanced therapy medicinal product contains human cells or tissues, Directive 2004/23/EC should apply only as far as donation, procurement and testing are concerned, since the further aspects are covered by this Regulation.

(15)

As regards the donation of human cells or tissues, principles such as the anonymity of both donor and recipient, altruism of the donor and solidarity between donor and recipient should be respected. As a matter of principle, human cells or tissues contained in advanced therapy medicinal products should be procured from voluntary and unpaid donation. Member States should be urged to take all necessary steps to encourage a strong public and non-profit sector involvement in the procurement of human cells or tissues, as voluntary and unpaid cell and tissue donations may contribute to high safety standards for cells and tissues and therefore to the protection of human health.

(16)

Clinical trials on advanced therapy medicinal products should be conducted in accordance with the overarching principles and the ethical requirements laid down in Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (6). However, Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products (7) should be adapted by laying down rules tailored to fully take into account the specific technical characteristics of advanced therapy medicinal products.

(17)

The manufacture of advanced therapy medicinal products should be in compliance with the principles of good manufacturing practice, as set out in Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use (8), and adapted, where necessary, to reflect the specific nature of those products. Furthermore, guidelines specific to advanced therapy medicinal products should be drawn up, so as to properly reflect the particular nature of their manufacturing process.

(18)

Advanced therapy medicinal products may incorporate medical devices or active implantable medical devices. Those devices should meet the essential requirements laid down in Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (9) and Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (10), respectively, in order to ensure an appropriate level of quality and safety. The results of the assessment of the medical device part or the active implantable medical device part by a notified body in accordance with those Directives should be recognised by the Agency in the evaluation of a combined advanced therapy medicinal product carried out under this Regulation.

(19)

The requirements in Directive 2001/83/EC as regards the summary of product characteristics, labelling and the package leaflet should be adapted to the technical specificities of advanced therapy medicinal products by laying down specific rules on those products. These rules should comply fully with the patient’s right to know the origin of any cells or tissues used in the preparation of advanced therapy medicinal products, while respecting donor anonymity.

(20)

Follow-up of efficacy and adverse reactions is a crucial aspect of the regulation of advanced therapy medicinal products. The applicant should therefore detail in its marketing authorisation application whether measures are envisaged to ensure such follow-up and, if so, what those measures are. Where justified on public health grounds, the holder of the marketing authorisation should also be required to put in place a suitable risk management system to address risks related to advanced therapy medicinal products.

(21)

The operation of this Regulation requires the establishment of guidelines to be drawn up either by the Agency or by the Commission. Open consultation with all interested parties, in particular Member State authorities and the industry, should be carried out in order to allow a pooling of the limited expertise in this area and ensure proportionality. The guidelines on good clinical practice and good manufacturing practice should be laid down as soon as possible, preferably during the first year after entry into force and before the date of application of this Regulation.

(22)

A system allowing complete traceability of the patient as well as of the product and its starting materials is essential to monitor the safety of advanced therapy medicinal products. The establishment and maintenance of that system should be done in such a way as to ensure coherence and compatibility with traceability requirements laid down in Directive 2004/23/EC in respect of human tissues and cells, and in Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components (11). The traceability system should also respect the provisions laid down in Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and the free movement of such data (12).

(23)

As science evolves very rapidly in this field, undertakings developing advanced therapy medicinal products should be enabled to request scientific advice from the Agency, including advice on post-authorisation activities. As an incentive, the fee for that scientific advice should be kept at a minimal level for small and medium-sized enterprises, and should also be reduced for other applicants.

(24)

The Agency should be empowered to give scientific recommendations on whether a given product based on genes, cells or tissues meets the scientific criteria which define advanced therapy medicinal products, in order to address, as early as possible, questions of borderline with other areas such as cosmetics or medical devices, which may arise as science develops. The Committee for Advanced Therapies, with its unique expertise, should have a prominent role in the provision of such advice.

(25)

Studies necessary to demonstrate the quality and non-clinical safety of advanced therapy medicinal products are often carried out by small and medium-sized enterprises. As an incentive to conduct those studies, a system of evaluation and certification of the resulting data by the Agency, independently of any marketing authorisation application, should be introduced. Even though the certification would not be legally binding, this system should also aim at facilitating the evaluation of any future application for clinical trials and marketing authorisation application based on the same data.

(26)

In order to take into account scientific and technical developments, the Commission should be empowered to adopt any necessary changes regarding the technical requirements for applications for marketing authorisation of advanced therapy medicinal products, the summary of product characteristics, labelling, and the package leaflet. The Commission should ensure that relevant information on envisaged measures is made available to interested parties without delay.

(27)

Provisions should be laid down to report on the implementation of this Regulation after experience has been gained, with a particular attention to the different types of advanced therapy medicinal products authorised.

(28)

The opinions of the Scientific Committee for Medicinal Products and Medical Devices concerning tissue engineering and that of the European Group on Ethics in Science and New Technologies have been taken into account, as well as international experience in this field.

(29)

The measures necessary for the implementation of this Regulation should be adopted in accordance with Council Decision 1999/468/EC of 28 June 1999 laying down the procedures for the exercise of implementing powers conferred on the Commission (13).

(30)

In particular, the Commission should be empowered to adopt amendments to Annexes I to IV to this Regulation and to Annex I to Directive 2001/83/EC. Since those measures are of general scope and are designed to amend non-essential elements of this Regulation and of Directive 2001/83/EC, they must be adopted in accordance with the regulatory procedure with scrutiny provided for in Article 5a of Decision 1999/468/EC. Those measures are essential for the proper operation of the whole regulatory framework and should therefore be adopted as soon as possible.

(31)

Directive 2001/83/EC and Regulation (EC) No 726/2004 should therefore be amended accordingly,