Transitional period for tissue engineered products expired: Regulation 1394/2007 applicable to all ATMP's

25 February 2013

Hanneke Later-Nijland

As from 31 December 2012, the transitional period for Tissue Engineered Products (TEPs) has expired. This means that from now on applications for a marketing authorisation for a TEP should follow the centralised procedure and should comply with all other requirements of Regulation (EC) No 1394/2007, which already apply to other advanced therapy medicinal products, such as somatic cell therapy medicinal products and gene therapy medicinal products. Please note that besides obligations, there are also several incentives for Small and Medium-sized enterprises with the intention to market TEPs in the European Union (which also apply to ATMPs in general), such as reductions in fees for marketing authorisations or requests for scientific advice by the European Medicines Agency (EMA).

Regulation (EC) No 1394/2007 

Regulation (EC) No 1394/2007 on advanced therapy medicinal products (ATMPs) has been applicable since 31 December 2008 and is a lex specialis, introducing additional provisions to those laid down in Regulation 2001/83/EC, as amended i.e. the Medicines Directive. The Regulation covers ATMPs which are intended to be placed on the market in Member States and, are either prepared industrially or manufactured by a method involving an industrial process [1].

Because of the novelty, complexity and technical specificity of ATMPs, specially tailored and harmonised rules are needed to ensure the free movement of these products within the European Union, and the effective operation of the internal market in the biotechnology sector [2].

ATMPs

ATMP's can be subdivided into three categories. The first group consists of the gene therapy medicinal products (GTMP's), which contain a recombinant nucleic acid as an active ingredient with a view to regulating, repairing, replacing, adding or deleting a genetic sequence. The second group consists of the somatic cell therapy medicinal products (sCTMP's). These either consist of cells or tissues which are substantially manipulated or, of cells or tissues which are not intended to fulfil the same essential function for the recipient as for the donor. The last category consists of the TEPs.

A TEP means a product that:

  • contains or consists of engineered cells or tissues, and

  • is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue.

A tissue engineered product may contain cells or tissues of human or animal origin, or both. The cells or tissues may be viable or non-viable. It may also contain additional substances, such as cellular products, bio-molecules, bio-materials, chemical substances, scaffolds or matrices.

Products containing or consisting exclusively of non-viable (human or animal) cells and/or tissues, which do not act principally by pharmacological, immunological or metabolic action, are excluded from this definition [3].

Furthermore, within the context of TEPs, tissues shall be considered ‘engineered’ if at least one of the following conditions is fulfilled:

  • the tissues have been subject to substantial manipulation, so that biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement are achieved.

  • Listed manipulations [4] - such as for example cutting, grinding, freezing or cryopreservation - are not considered as substantial manipulations.

  • the tissues are not intended to be used for the same essential function or functions in the recipient as in the donor.

As a result of the expiry of the transitional period for TEPs as of 31 December 2012 [5], these products are now subject to the centralised authorisation procedure, involving a single scientific evaluation of the quality, safety and efficacy of the product. Since the evaluation of ATMPs requires very specific expertise, a Committee for Advanced Therapy (CAT) has been established, which will prepare a draft opinion on the quality, safety and efficacy of each ATMP for final approval by the Committee for Medicinal Products for Human Use (CHMP).

The CAT shall endeavour to reach scientific consensus. However, if such consensus cannot be reached, the CAT shall adopt the opinion of the majority of its members. The draft opinion shall mention the divergent positions and the grounds on which they are based [6].  Where the scientific opinion on an ATMP drawn up by the CHMP is not in accordance with the draft opinion of the CAT, the CHMP shall attach a detailed explanation of the scientific grounds for the differences. Please note that such explanation may be obtained following a request pursuant to Regulation (EC) No 1049/2001 regarding public access to European Parliament, Council and Commission documents, since documents held by the EMA also fall under the scope of this Regulation - and it is likely that the EMA will possess such explanation [7]. As with all medicinal products, marketing authorisations for ATMPs are granted by the European Commission.

Traceability

The holder of a marketing authorisation for an ATMP, shall establish and maintain a system ensuring that the individual product and its starting and raw materials, including all substances in contact with the tissue it may contain, may be traced throughout the sourcing, manufacturing, packaging, storage, transport and delivery through the hospital, institution or private practice where the product is used. Besides, the marketing authorisation holder shall keep the data referred to for a minimum of 30 years after the expiry date of the product, or longer if required by the Commission as a term of the marketing authorisation. Please note that in case of bankruptcy or liquidation of the marketing authorisation holder, and in case the authorisation is not transferred, the data shall be transferred to the Agency [8]. Upon withdrawal, suspension or revocation of the marketing authorisation, its holder shall remain subject to such obligations. 

The hospital, institution or private practice where the advanced therapy medicinal product is used, shall establish and maintain a system for product traceability. The system should allow linking of each product to the patient receiving it and vice versa.

Pharmacovigilance

In addition to the requirements for pharmacovigilance pursuant to Regulation (EC) No 726/2004, the applicant shall detail the measures aiming to ensure the follow-up of efficacy of ATMPs and of its adverse events. Please note that infringement of some pharmacovigilance obligations pursuant to Regulation (EC) No 726/2004 may be financially penalized [9]. 

In case of particular causes of concern, a risk management system may be required as part of the marketing authorisation in order to identify, characterise, prevent or minimise risks related to ATMPs, including an evaluation of the effectiveness of that system. The (relatively) new [10] pharmacovigilance rules for medicinal products already obliges the applicant of a marketing authorisation to introduce such a system for the medicinal product concerned - proportionate to the identified and potential risks [11]. 

In addition, specific post-marketing studies may be carried out by the holder of the marketing authorisation and submitted for review to the EMA [12].  Again, the new pharmacovigilance rules allow for the Agency to impose an obligation on the marketing authorisation holder to conduct a post authorisation safety or efficacy study even after the marketing authorisation has been granted [13]. 

Specific study requirements for tissue engineered products

Pursuant to Annex I of Directive 2001/83/EC [14] the following study requirements pertain to TEPs. As regards pharmacokinetic studies, it is stipulated that in case conventional pharmacokinetic studies are not relevant for TEPs, the biodistribution, persistence and degradation of the tissue engineered product components shall be addressed during the clinical development. Besides, pharmacodynamic studies shall be designed and tailored to the specificities of TEP. The evidence for the ‘proof of concept’ and the kinetics of the product to obtain the intended regeneration, repairing or replacement shall be provided. Suitable pharmacodynamic markers, related to the intended function(s) and structure shall be taken into account. Finally, safety studies shall address, for example, distribution and engrafting following administration, ectopic (displaced) engraftment, and oncogenic transformation.

Incentives for Small and Medium-sized Enterprises (SMEs)

Next to many obligations and requirements, the regulation also contains several incentives aimed at SMEs. The applicant or holder of a marketing authorisation may request advice from the EMA on the design and conduct of the pharmacovigilance and of the risk management system – a 90% reduction for SMEs and a 65% reduction for other applicants shall apply for such scientific advice or for advice on the conduct on the tests and trials necessary to demonstrate the quality, safety and efficacy of the ATMPs [15]. 

Any applicant developing an ATMP may request a scientific advice of the EMA, with the purpose of determining whether the product falls –on scientific grounds- within the definition of an ATMP. After consultation with the Commission, the EMA shall deliver such recommendation within 60 days after receipt of the request. Of interest, the EMA shall publish summaries of the recommendations, after deletion of information of commercial confidential nature [16].

The fee for marketing authorisation shall be reduced by 50% if the applicant is a hospital or a SME and is able to prove that there is a particular public health interest in the ATMP concerned, in the European Union. This also accounts for fees charged by the Agency for post-authorisation activities in the first year following the granting of the marketing authorisation for the ATMP [17].

Two exceptions to a marketing authorisation: the hospital exemption and clinical research 

However, there are two exceptions to applying a TEP (or an ATMP in general) without being granted marketing authorisation pursuant to the regulation. First, some TEPs may be prepared in a hospital through the hospital exemption. Second, some TEPs may be used within the scope of clinical research.

TEPs which are prepared in a hospital based on the hospital exemption are regulated by national law. In general, it can be said that it covers the non-routine preparation of ATMPs according to specific quality standards and which are to be 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 an individual patient. In the Netherlands, such permission under the hospital exemption is granted by the Dutch Health Care Inspectorate (IGZ). A preparation performed for a maximum of 5 patients is considered to fulfil the condition that it was 'ordered for a specific patient'.

The application for permission to prepare an ATMP based on the hospital exemption may be submitted by the board of a pharmaceutical company, or the managing board of a hospital. The applicant has to be employed by the organisation for which the hospital exemption shall apply. Finally, the preparation of an ATMP must take place according to the principles of Good Manufacturing Practice (GMP).

An ATMP investigated within the scope of clinical research with humans is considered an investigational medicinal product (IMP). Therefore, the applicable legislation applies, such as Regulation 2001/20/EC – the guidelines of 'Good Clinical Practice' (GCP) have to be followed and approval of (for example) the study protocol and the Informed Consent form by a medical-ethical committee has to be obtained in advance.  

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[1] Consideration (6) of Regulation (EC) No 1394/2007, as amended, referring to Title II of Directive 2001/83/EC, as amended.
[2] Consideration (5) of Regulation (EC) No 1394/2007, as amended. 
[3] Article 2(1) under (b) of Regulation (EC) No 1394/2007, as amended. 
[4] See Annex I of Regulation (EC) No 1394/2007, as amended.
[5] Article 29(2) of Regulation (EC) No 1394/2007, as amended.
[6] Article 8 of Regulation (EC) No 1394/2007, as amended. 
[7] Article 73 of Regulation (EC) 726/2004, as amended. 
[8] Article 15 of Regulation (EC) No 1394/2007, as amended.
[9] See Regulation (EC) No 726/2004, as amended, and Regulation (EC) No 658/2007, as amended by Regulation (EC) No 488/2012. 
[10] July 2012
[11] Article 6 of Regulation (EC) No 726/2004 as amended and article 8(3)(iaa) of Directive 2001/83/EC, as amended by Directive 2010/84/EC. 
[12] Article 14 of Regulation (EC) No 1394/2007, as amended.
[13] Article 10a of Regulation (EC) No 726/2004, as amended by Regulation (EC) No 1235/2010. 
[14] Annex I of Directive 2001/83/EC, as amended under 5.3.3.
[15] Article 16(1) and (2) Regulation (EC) No 1394/2007 as amended, and article 57(1)(n) of Regulation (EC) 2004/627, as amended.
[16] Article 17 Regulation (EC) No 1394/2007, as amended.
[17] Article 19 Regulation (EC) No 1394/2007, as amended.

 

 

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