Classification of RegMed products
European regulatory regimes for Regenerative Medicine (RegMed) 
Important EU Regulations and Directives for medicinal products and RegMed
Realisation of EU-requirements in the German Medicines Act
Regulatory aspects of cardiac stem cell therapy

Classification of RegMed products

Gaining new knowledge about regenerative and repair mechanisms of the human body has led to novel innovative and complex products. Regenerative Medicine (RegMed) describes the application of living cells and tissues, regenerative agents and materials in the field of human medicine. The therapeutic effects of these products/therapies are due to stimulation of the body´s own regenerative and repair mechanisms. Alternatively, these products are applied as biological replacements.

RegMed poses new challenges for the authorities: the regulations should not contain any “grey areas”, they should meet the specific requirements of the RegMed products, ensure the protection and safety of the patients, and finally they should not affect the medical progress gained by research and development.
It is advisable to deal with the regulations and to classify the product to be developed at an early stage, if the development of stem cell and other innovative therapies is considered. Depending on the classification of the products the corresponding procedures of establishing it on the market differ from each other. First of all, the following different categories need to be considered:

• Biomaterials and active implantable devices, classified as medical devices and regularized by the Medical Devices Directives,
• Regenerative Molecules, which can be „small molecules“ or biologicals, which meet the European regulations for Medicinal Products, in Germany the German Medicines Act (AMG),
• Living Cell Based Medicinal Products: within this category the group of gene therapy-(GT), somatic cell therapy-(SCT) and tissue engineered- products (TEP) are classified as Advanced Therapy Medicinal Products. These are subject to EU-regulation 1394/2007/EG (ATMP-Regulation). The rules for living cell-based products, which are not classified as ATMPs or defined as exceptions of those, are laid down by national law of the Member States.

Combinations of medical devices or medicinal products with living cell based medicinal products are classified as tissue engineered products. However each of these components has to meet its corresponding regulations (MPG…)

The following questions are of importance for the classification of RegMed products:

• Does the product meet the definition of an ATMP according to the ATMP-Regulation? (Definition)
• Does the product fall within the scope of the ATMP-Regulation? (Scope)

The European Medicines Agency (EMA) as well as national authorities (in Germany the PEI information office) provide assistance regarding the classification.

back to top

European Regulatory Regimes for Regenerative Medicine (RegMed)

Regulations for development, production and approval of medicinal products are largely harmonized within the EU. The European Medicines Agency (EMA), founded 1995, is responsible for evaluation and monitoring of medicinal products in Europe. The Committee for Medicinal Products for Human Use (CHMP) of the EMA delivers after evaluation the opinion to the European Commission for final approval.

The legal bases are mainly two fundamental instruments: Regulations and Directives. EC-Directives have to be transposed into national law of each Member State (MS), whereas EU-Regulations are directly valid for all EU-member states. Furthermore there are technical directives, guidelines and others.

At the end of December 2008, the EC-Regulation 1394/2007/EG (ATMP-Regulation) for cell and tissue based therapies came into effect, which regulates the Advanced Therapy Medicinal Products (ATMP). These include gene therapy medicinal products, somatic cell therapy medicinal products, and tissue engineered products, as well as “combined Advanced Therapy Medicinal Product” which contain medicinal products or medical devices as components.

To meet the specifics of the ATMPs the ATMP-Regulation has several elements: it amends other aspects of European medicines law, contains provisions and rules and claims for new supporting activities and incentives by the MS-authorities and tasks the European Commission and the EMA with specific implementation steps.

The EU-Commission and the EMA are currently working on the realisation of these requirements. Explanations of the implementation concept as well as the status quo can be found on the website of the EMA.

 Market Authorisation (MA)

According to the new regulation ATMPs need to obtain MA from the European Commission. They have to be generally evaluated within the scope of the central European procedure by the European Medicines Agency. Beside the Committee for Medicinal Products for Human Use (CHMP) a new specific and multidisciplinary expert committee ( Committee for Advanced Therapies, CAT) has been established for the evaluation of ATMPs. The approval by the EU-Commission permits market access in the entire EU.

The scope of the ATMP-Regulation is limited to products which are intended to be placed on the market in MS and which are either prepared industrially or manufactured by a method involving an industrial process. If an ATMP is not prepared industrially or manufactured by a method involving an industrial process, and not intended to be placed on the market in the Member State it is out of the scope of the ATMP-Regulation. For these ATMPs applies Art. 28(2) of the ATMP-Regulation, the so-called ‘Hospital Exemption’. Member States are requested to lay down rules for authorising these products by the national Competent Authority whilst at the same time ensuring that relevant Community rules related to quality and safety are not undermined.

Furthermore, the regulation of products made of living cells and tissues which do not comply with the definition of an ATMP (according to ATMP-Regulation) is also subject to national legislation of the member states.

Transitional Period

For ATMPs which were “legally on the market” in accordance with national or community legislation on 30 December 2008 a transitional period is granted:
3 years for SCT and GT (until 30 December 2011) and
4 years for TEPs (30 December 2012).

back to top

Important EU-Regulations and Directives for medicinal products and RegMed (pdf files)

• Regulation 1394/2007/EC (ATMP-Regulation)
• Directive 2004/23/EC: Definition of standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells
• Directive 2006/17/EC: (implementing Directive 2004/23/EC regarding technical requirements for the donation, procurement and testing of human tissues and cells)
• Directive 2006/86/EC: (implementing Directive 2004/23/EC regarding traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells)
• Directive 2001/83/EC: Community code relating medicinal products for human use
  + Annex I Directive 2003/63/EC
  + in addition to Annex I (regarding ATMP): Directive 2009/120/EC
• Regulation 726/2004/EC (laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency: Regulation of central authorisation of AM)
• Directive 2001/20/EC and Directive 2005/28/EC (GCP-Guideline: laying down principles and 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)
• Directive 2003/94/EC (GMP-Guideline: laying down principles and guidelines of good manufacturing practice with respect to medicinal products for human use and investigational medicinal products for human use) 

back to top

Realisation of EU-requirements in the German Medicines Act

In Germany medicinal products are regulated by the German Medicines Act ( „Gesetz über den Verkehr mit Arzneimitteln“, AMG). The 15^th amendment of the AMG (since summer 2009) implements the content of the ATMP-Regulation as well as national regulations for other cell- and tissue-products and rules for specific exemptions.

For an ATMP within the definition and the scope of the ATMP-Regulation the following rules apply EU-wide:

• GMP-Manufacturing [§13 AMG] (nationally authorised, in Germany by the local authorities)
• GCP clinical trials [§40 AMG] ((nationally authorised, in Germany by the Paul-Ehrlich-Institute)
• Central EU-Approval (M.A. by the EU-Commission)
  [§21 AMG; Reg. (EC) 726/2004] → EU-wide commercialisation

For an ATMP within the definition but outside scope of the ATMP-Regulation („Hospital exemption“) the following rules apply for Germany:

• GMP-Manufacturing [§13 AMG] (nationally authorised by the local authorities)
• Authorisation according § 21a AMG by PEI („Mini-Approval“) → application only in a hospital of the same MS (individually for a patient by his/her treating physician)

If the product is not an ATMP, then in Germany it could be:

• a medical device, for which the Medical Devices Act (MPG) is valid.
• a tissue/-product, for which authorisation according to §20b/20c/21a AMG is required
• the exemption according to AMG §4a(3), i.e., a tissue which was taken from a patient during a treatment and which is to be returned to the patient without changing its material composition.

back to top

Regulatroy aspects of cardiac stem cell therapy

The stem cells which are therapeutically applied at the RTC fulfil definition and scope of the ATMP-Regulation. Therefore, the central EU approval is mandatory and clinical trials have to proof the safety and efficacy of the cardiac stem cell therapy.

Dose, safety and efficacy have been investigated during clinical Phase I/II and II trials since 2001 at Rostock. Based on promising results, the Paul-Ehrlich-Institute authorised the RTC team to continue with a Phase III trial. The first patient has been admitted in autumn 2009. Based on the results of this study, the RTC plans to apply for a European-wide market authorisation.

At the same time further individual cardiac stem cell therapies have been applied since 2006 at the RTC. The medical care of the patients and the documentation of the treatment are geared to study conditions. In order to evaluate the long-term safety and efficacy of the therapy the patients will be continuously invited to follow-ups for an extended period.

back to top