GTMPs contain a recombinant nucleic acid, which is administered to human beings aiming at regulating, repairing, replacing, adding, or deleting genetic information. Moreover, it is essential that the intended therapeutic, prophylactic, or diagnostic effect is directly related to the recombinant nucleic acid or the product of its expression [2]. For example, reprogramming a differentiated cell to a pluripotent stem cell by genetic modification alone may not be sufficient to classify the resulting product as GTMP, as the genetic modification is not necessarily contributing to the therapeutic effect. It is important to note that with the amendment of Directive 2001/83/EC by Directive 2009/120/EC, vaccines against infectious diseases, irrespective whether they are used in a prophylactic or therapeutic setting, are not considered as GTMPs. Thus, for example, a particular active substance could be either vaccine or GTMP depending on whether it is used to treat a virus infection causing cancer or cancer caused by the virus infection.

sCTMPs and TEPs have in common that they contain “engineered” cells (which may be viable or non-viable). In this context engineered means that the cells are substantially manipulated or are not intended to be used for the same essential function in the recipient as in the donor. The latter is commonly referred to as “nonhomologous” use. However, sCTMPs and TEPs differ in the purpose of administration. TEPs are administered for regenerating, repairing, or replacing a human tissue. sCTMPs are used for treating, preventing, or diagnosing a disease through the pharmacological, immunological, or metabolic action of the cells. In addition, Regulation 1394/2007/EC defines combined ATMPs as products integrating a medical device into an ATMP that contains viable cells or cells being nonviable but being associated with the primary action of the medicinal product in the human body [1].

Apparently, for classification it is crucial to evaluate whether cells are substantially manipulated or used in a nonhomologous way. To further explain the meaning of these terms and the approach for classification, a “Reflection paper on classification of advanced therapy medicinal products” is being developed as a guidance document [5]. However, in specific cases it still may be rather challenging to unanimously classify a product, especially in case of autologous cells/tissues taken from the patient, prepared in a more or less substantial process and used for not exactly the same purpose as before. Therefore, Regulation 1394/2007/EC in Article 17 implemented a procedure, by which applicants can request from the European Medicines Agency (EMA)/CAT a scientific recommendation whether or not a specific product may be classified as ATMP. Since implementation of the procedure in 2009, more than 120 requests for classification have been submitted to the CAT. Only when classified as ATMP, the CAT is involved in the evaluation process for marketing authorization of the product.

The certification procedure was implemented as an incentive to support the development of ATMPs by small- and medium-sized enterprises (SME). Since obtaining a European marketing authorization for an ATMP may be a time-consuming and strenuous effort for an SME, certification is intended to provide an intermediate milestone to be achieved. The SME may submit to the EMA/CAT available quality and nonclinical data for scientific evaluation. If the data are in line with the requirements as set out in Directive 2001/83/EC [3], a certificate will be issued stating compliance of data with requirements. For such a certificate it is not mandatory to submit a full quality or nonclinical dossier; a certificate may be achieved also for parts of the data with additional data still needed to be generated. Detailed guidance on the certification procedure and the minimum data set necessary to apply for certification has been provided by EMA [6, 7].

Application for and granting of a certificate was intended to support SMEs in entering into a first dialogue with the regulatory agency and to increase the company’s value for potential investors. However, so far only a few certifications have been applied for. In view of the stakeholders the main disadvantages related to this procedure are the absence of a link between certification and marketing authorization and the exclusion of academia and research groups from certification [8].

As for other medicinal products there are several procedures available for applicants to obtain feedback and support from regulatory authorities when challenges or questions arise during the developmental phase of an ATMP or when preparing for Marketing Authorization Application (MAA). Later in development and especially when crucial decisions have to be taken in view of the intended MAA, the EMA scientific advice procedure comes with the advantage of giving the applicant a harmonized view, by regulators throughout the EU, on the specific issues addressed. However, since science and state of the art may develop and progress, the advice given cannot be binding with respect to future evaluations and decisions in the context of an MAA. During early stages of development, advice is mostly sought from national regulatory authorities. This approach may be triggered by various aspects including the national responsibility for the approval of clinical trials and the lower costs and workload associated with a national scientific advice procedure. The latter is an important aspect in view of the fact that ATMPs are quite often developed by academic institutions or SMEs with only limited financial and regulatory capacities. To effectively support applicants in the development of ATMPs, the national advice procedures should be not too formal or associated with an excessive workload but flexible and easy to handle. In Germany, for example, an innovation office was established to serve this purpose for ATMPs.

The centralized procedure for obtaining a marketing authorization for a medicinal product was initially established to ensure a harmonized evaluation and an EU-wide availability of innovative products. In contrast to multifold national applications and authorizations, the centralized procedure is led by the EMA and includes a collaborative evaluation of an MAA by all Member State authorities, resulting in an opinion of the CHMP. Finally the European Commission grants a marketing authorization which is valid throughout all Member States of the EU. This procedure was implemented by Regulation 726/2004/EC [9]. It applies to ATMPs as modified by Regulation 1394/2007/EC, which details requirements for and the procedure of an MAA [1]. While the CHMP is still responsible for issuing the final opinion for granting a marketing authorization, assessment of the application and presentation of the draft opinion are performed by the CAT, based on its ATMP-specific expertise. Accordingly, two CAT members are assigned as the Rapporteur and Co-rapporteur for the evaluation of the dossier by their own assessment teams. Very recently, a pilot study was initiated by setting up multinational assessment teams with the view of broadening the involvement of EU Member States and to foster inclusion of the best available expertise for evaluation of an ATMP. Beside the central role of the CAT in the assessment of the application, the authorization procedure is quite similar to that for other medicinal products. The Rapporteur and Co-rapporteur perform independent assessments of the dossier, which is presented according to the Common Technical Document (CTD) format, and prepare assessment reports including questions addressing deficiencies and open issues of the application. After discussion between the expert committees and consolidation, a list of questions is issued by CAT and CHMP and forwarded to the applicant in order to resolve the issues raised. The procedure is restarted when the applicant’s response document is submitted. The response is jointly evaluated by the Rapporteur and Co-rapporteur and outstanding issues which need to be further addressed and resolved are identified, leading to another cycle of question, response, and evaluation. If the applicant cannot resolve all issues, an oral explanation meeting provides the possibility to directly address and discuss all open questions before the final considerations by CAT/CHMP and the adoption of an opinion. The opinion is drafted by the CAT and forwarded to the CHMP for further discussion and adoption. Marketing authorization finally will be issued by the European Commission. Specific issues and requirements for the scientific evaluation of an MAA for ATMPs are addressed in Sect. 10.3.

There are several regulatory procedures for ATMPs, which are not in the remit of the CAT but fall under the responsibility of national competent authorities (NCA).

One example is the approval of clinical trials which is performed by each individual Member State, in which the clinical trial is proposed to take place. However, by issuing the Clinical Trials Directive 2001/20/EC [10], the European Parliament and the Council have set the basic rules and procedures for application of a clinical trial and its assessment. As with all Directives, these provisions are not directly legally binding in the Member States but need to be implemented in the national legislation. In Germany, the EU Directive was transposed in the sixth chapter of the German Medicinal Products Act (Arzneimittelgesetz, AMG) [11] and further detailed in the subordinated “Ordinance on the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for use in humans” [12].

The national implementation allows some modification and further refinement of the basic principles, and thus some national particularities in the procedure for approval of clinical trials still remain. To facilitate the conduct of multinational trials, a voluntary harmonization procedure (VHP) was implemented by the clinical trial facilitation group (CTFG). This procedure includes a harmonized evaluation of the application by the involved Member States as a first step, followed by the national implementation of the collective decision as a second step. Since its implementation in 2011, numerous VHP procedures for ATMPs were conducted, which confirmed this approach as a valid tool for facilitating the conduct of multinational trials.

Very recently, in April 2014 a new regulation for clinical trials, Regulation 536/2014/EC, has been adopted and will come into force after a transitional period, but not before May 2016 [13]. This new regulation is, by definition, immediately binding for all EU Member States and does not need to be implemented into national law. The new procedure aims at a continuous facilitation of the conduct of clinical trials through an appropriate and fast evaluation of clinical trial applications by avoiding parallel or separate evaluations in the EU Member States.

A second example for national regulatory procedures for ATMPs is based on Article 28 of Regulation 1394/2007/EC that makes a special provision for a “national” approach to ATMPs, usually called “hospital exemption” (HE) [1]. The term itself may be misleading since it is not restricted to hospitals. Instead, it addresses ATMPs, which are manufactured on a nonroutine basis for an individual patient following an individual medical prescription in a given Member State. It was recognized that for ATMPs with a patient-centered and local perspective, a centralized authorization procedure via CAT and CHMP would not be adequate and may even hinder the availability of new innovative therapies. Thus, such ATMPs are subjected to the national responsibility of the Member States. For implementation of Article 28 at the national level, different approaches were followed. While GMP-compliant manufacturing and the exclusive clinical use of the ATMP in the Member State in which it is manufactured are common principles, the requirements and procedure for granting the HE may differ between the Member States. For example, in Germany a dedicated approval procedure was established which is essentially based on evaluation of the benefit-risk ratio of the product. Compared to a centralized MAA, however, it is taken into account that limited clinical data may be available and thus a higher uncertainty regarding the benefit-risk ratio may be acceptable for granting the HE. It was argued that this procedure might be used by applicants to circumvent the challenges associated with obtaining a centralized marketing authorization. However, this procedure is limited to specific, legally defined ATMPs with a more individual and local perspective and restrictions with respect to commercialization of the medicinal product. Thus, the HE may be more appropriate for these ATMPs, while for others a centralized marketing authorization is more adequate. In line with this, the HE should be regarded as complementing rather than competing with the centralized marketing authorization.

Some characteristics of ATMPs require specific considerations when an ATMP is evaluated in a clinical setting. Therefore, the European Commission prepared detailed guidance on good clinical practice (GCP) specific to ATMPs [15], which is supplementing the detailed GCP guidelines set out in Commission Directive 2005/28/EC [16]. Key aspects are the procurement of tissues and cells, their full traceability, and the requirements for long-term follow-up on safety and efficacy. This latter point is discussed in subchapter Sect. 10.3.4.2.

If an ATMP contains human tissue or cells, the risk of transmitting an infectious disease from the donor to the recipient of the ATMP has to be minimized by careful donor selection and testing of each donation. Therefore, Regulation 1394/2007/EC [1] defines that donation, procurement, and testing of human tissues or cells need to be performed in accordance with the tissue and cell legislation including Directive 2004/23/EC [17], the implementing Directive 2006/17/EC [18], and Directive 2012/39/EU [19] that amends Directive 2006/17/EC with regard to human T-lymphotropic virus type I (HTLV-I) antibody testing. While these directives apply to human tissues and cells including hematopoietic peripheral blood, umbilical-cord and bone-marrow stem cells, reproductive cells, fetal tissues and cells, and embryonic and adult stem cells, blood and blood products are regulated separately in Directive 2002/98/EC [20].

Each ATMP containing biological material from a donor should be allocable from the donor to the individual subject who received the medicinal product and vice versa. This requires that coding systems are introduced that allow anonymized traceability of the ATMP from procurement of the tissue or cells, manufacturing, testing, and storage to distribution and eventually administration to the recipient or disposal. Thereby, the traceability system in place should be complementary to, and compatible with, the requirements laid down in Directive 2004/23/EC [17] and Directive 2002/98/EC [20] for tissue and blood establishments. To guarantee traceability the following bidirectional links need to be established: a link between the donor source and the donation at the tissue establishment, a link between the donation and the product at the manufacturing site, and a link between the ATMP and the treated individual at the investigator site. All traceability data need to be archived for a minimum of 30 years after the expiry date of the product [21].