The ATMP Regulation

Before the ATMP Regulation, gene-therapy and cell-therapy products were assessed under the general centralised procedure governed by Regulation (EC) No 726/2004 and the Community code for medicinal products (Directive 2001/83/EC). The existing rules were not designed for living cells, viral vectors or engineered tissue constructs, creating legal uncertainty for developers and uneven application across Member States.

Regulation (EC) No 1394/2007 addressed this by creating a lex specialis (recital 6): a tailored layer of rules that sits on top of the existing pharmaceutical acquis but overrides it where specific ATMP provisions apply. The Regulation simultaneously amends Directive 2001/83/EC (inserting the hospital exemption via new Article 3(7)) and Regulation (EC) No 726/2004 (adding ATMPs to the mandatory centralised scope and establishing the CAT). This cross-cutting structure means that understanding the ATMP Regulation requires knowledge of both of those parent instruments.

ATMPs are medicinal products based on genes, cells or tissues. Their mode of action is fundamentally different from small-molecule drugs or conventional biologics: a gene-therapy product may permanently modify a patient's DNA; a somatic cell therapy product may trigger an immune response calibrated to a specific tumour; a tissue-engineered product may integrate with and regenerate damaged tissue over months or years. These characteristics create challenges that standard pharmacokinetic models do not easily accommodate:

• Long-term efficacy data require extended follow-up beyond conventional trial timelines
• Manufacturing variation between batches is inherently high because living cells are used
• Traceability from donor to recipient (and reverse) is critical for detecting late adverse events
• Many ATMPs target rare diseases, making large randomised trials structurally impossible
• Products combining cells with medical devices (scaffolds, matrices) straddle two regulatory regimes

The Regulation was adopted under Article 95 TEC (now Article 114 TFEU), the internal market approximation basis, by co-decision procedure (Article 251 TEC). It was signed at Strasbourg on 13 November 2007 by EP President Hans-Gert Pottering and Council President Mario Lobo Antunes (Portuguese Presidency). Published in OJ L 324 on 10 December 2007, it entered into force on 30 December 2007 and applied from 30 December 2008, giving industry and competent authorities one year to prepare. The Regulation has EEA relevance, so Norway, Iceland and Liechtenstein are also bound.

Where an ATMP contains human cells or tissues, those cells or tissues must be donated, procured and tested in accordance with Directive 2004/23/EC (the Tissues and Cells Directive). This means the donation must be voluntary and unpaid, quality and safety standards must be met at collection, and donor testing (for infectious disease markers) must be performed. The requirement applies both to autologous products (where the donor and recipient are the same person) and allogeneic products.

Article 12 adds that the labelling of an ATMP containing human cells or tissues must indicate whether the product is autologous or allogeneic. For autologous products, the label must state "For autologous use only" and include a unique patient identifier, so that product and patient can always be matched without revealing the donor's identity to the recipient or the recipient's identity to a third party.

Clinical trials of ATMPs must comply with Directive 2001/20/EC (the Clinical Trials Directive, now succeeded by Regulation (EU) No 536/2014 for new trials). The Regulation mandates that the Commission shall adopt guidelines specific to ATMPs on good clinical practice, taking into account the specificities of these products. These ATMP-specific GCP guidelines address issues such as long-term follow-up periods, endpoints appropriate for cell-based therapies and risk-adapted trial designs for rare-disease targets.

ATMPs must be manufactured in accordance with good manufacturing practice (GMP). The Regulation grants the Commission power to adapt existing GMP guidelines or adopt ATMP-specific GMP guidelines, taking into account the specificities of these products, particularly the use of living cells, the need for donor traceability, and the difficulties in applying conventional batch-release approaches where batches may be produced on a patient-specific basis. In practice, the Commission has adopted guidance documents via the EudraLex Volume 4 pharmaceutical legislation guidelines.

Where an ATMP contains an integral device part, the device component must meet the relevant essential requirements of the applicable medical-device directive (Directives 90/385/EEC or 93/42/EEC, now succeeded by Regulations (EU) 2017/745 and 2017/746 for new products). The entire combined product is authorised through the ATMP route via the EMA. The competent authority or notified body that has assessed the device component issues an opinion on that part; the CAT takes that opinion into account when drafting its overall scientific opinion, and the CHMP endorses the full product authorisation. This prevents regulatory arbitrage by which a combination product might be classified as a device to avoid the medicine MA route.

The ATMP Regulation creates a two-stage scientific evaluation within the EMA. When a marketing-authorisation application for an ATMP is submitted, the Committee for Advanced Therapies (CAT) carries out the primary scientific assessment. The CAT examines the quality, safety and efficacy data in the dossier, taking into account the specific features of ATMPs described above. At the end of its evaluation, the CAT adopts a draft opinion on whether to recommend granting, refusing, or varying the marketing authorisation.

This draft opinion is then transmitted to the Committee for Medicinal Products for Human Use (CHMP). The CHMP takes the CAT's draft opinion into account, and in the absence of any scientific objection, it ratifies that draft opinion into its own final opinion within 30 days. If the CHMP has grounds for scientific disagreement, a consultation mechanism between the two committees is triggered. The final CHMP opinion then goes to the European Commission, which takes the formal marketing-authorisation decision under Regulation (EC) No 726/2004. The CAT is also consulted on re-examination procedures.

The centralised procedure is mandatory for all ATMPs throughout the EU. Article 27 of the Regulation inserts a new point 1a into the Annex of Regulation (EC) No 726/2004, placing ATMPs in the list of products for which the centralised procedure is compulsory. This prevents the fragmented approval landscape that would result from national marketing-authorisation applications and ensures uniform access conditions across Member States.

For combined ATMPs, the EMA evaluates the product as a whole under the ATMP MA procedure. Where a competent authority or notified body has already assessed the device component, the CAT requests an opinion from that body on the conformity of the device part. The CAT then takes that opinion into account in its overall assessment. If no notified-body assessment has been conducted, the CAT may itself assess the device part or request that a notified body undertake such an assessment. The goal is to ensure that applicants do not face a fragmented dual-track assessment (medicine MA plus device CE marking) for a truly integrated product.

Given that ATMPs often target serious or life-threatening conditions and may be granted marketing authorisation on the basis of limited long-term data, the Regulation requires marketing-authorisation holders to establish and maintain a system of risk management covering the measures necessary to mitigate identified and potential risks. As a condition of the authorisation, the CAT and CHMP may require the holder to establish a post-authorisation efficacy study (PAES) and a post-authorisation safety study (PASS), tracking patients for periods that may extend well beyond the typical pharmaceutical follow-up timeframes. The specific measures required are set out in the risk management plan annexed to the marketing authorisation.

The holder must also comply with the general pharmacovigilance requirements of Regulation (EC) No 726/2004 and Directive 2001/83/EC, adapted as appropriate to the ATMP context: for example, spontaneous adverse-reaction reporting must account for events that may emerge years after treatment, and patient registries are frequently used as the post-authorisation data-collection infrastructure.

Article 15 imposes the most stringent traceability requirement in EU pharmaceutical law. Marketing-authorisation holders must implement and maintain a system ensuring that the ATMP and its raw materials and starting materials (including all substances of biological origin) can be traced bidirectionally: from the product to the patient who received it and from the patient back to the product. The traceability system must be capable of identifying every patient who received a specific batch or lot of the ATMP, and every ATMP received by a specific patient.

Critically, traceability data must be retained for a minimum of 30 years after the expiry date of the product (Article 15(4)). This exceptionally long retention period reflects the potential for delayed adverse events following permanent genetic modification or long-lived cell engraftment. The obligation extends to distributors, healthcare institutions and any other party in the supply chain. For autologous products, the unique patient identifier on the label serves as the traceability anchor.

Any developer, not just SMEs, may request a classification recommendation from the CAT to confirm whether a product qualifies as an ATMP and, if so, which type (gene therapy, somatic cell therapy, TEP, or combined ATMP). The CAT must issue its recommendation within 60 days of the request. This pre-development opinion gives developers regulatory certainty before investing in the full dossier and manufacturing development. If the developer disagrees with the CAT's classification, it may refer the matter to the CHMP. The classification opinion is not legally binding for the purpose of the subsequent MA assessment but provides a strong indication of the regulatory path that will apply.

The ATMP Regulation establishes the Committee for Advanced Therapies as a specialist scientific committee within the EMA, one of the agency's seven scientific committees. The CAT is not a standalone body but is constituted under the EMA's organisational structure, with its secretariat provided by the EMA and its procedures governed by the EMA's rules of procedure. The CAT began operations on 30 December 2008 (the date of application of the ATMP Regulation).

The CAT's composition reflects the cross-cutting scientific disciplines involved in ATMPs. Article 21 specifies that the committee must include:

• One member nominated by each Member State, selected for expertise in gene therapy, somatic cell therapy or tissue engineering
• Two members and two alternates nominated by the European Parliament
• Two members and two alternates nominated by the Commission to represent clinicians
• Two members and two alternates to represent patients' associations
• At least two members with expertise in medical devices (the device experts are mandatory given the prevalence of combined ATMPs)

This multidisciplinary design ensures that the committee can assess gene vectors, manufacturing processes, tissue scaffold biocompatibility and device safety within a single review, without requiring the product to be split across separate regulatory tracks.

CAT members are subject to the same conflict-of-interest rules as CHMP members, extended to capture the ATMP sector specifically. Members must annually declare any interests that could affect their impartiality, including in the biotech sector and the medical-device sector. A member with a conflicting interest must not participate in scientific assessment or vote on the product concerned. Declarations are publicly accessible on the EMA website. This broader conflict-of-interest perimeter recognises that ATMP companies and medical-device companies increasingly converge, especially in the combined-ATMP space.

The principal tasks of the CAT are: (a) carrying out the scientific evaluation of ATMPs and drafting opinions for the CHMP; (b) advising the CHMP on whether a product qualifies as an ATMP (classification); (c) providing scientific recommendations on any scientific matter related to ATMPs at the request of the Commission, the CHMP or a Member State; and (d) supporting the development of ATMPs through scientific advice and the certification scheme for SMEs. The CAT also provides advice on post-authorisation measures, risk management plans and risk-minimisation activities for authorised ATMPs.

The hospital exemption is consistently identified as the most contested aspect of the ATMP framework. Critics argue that the conditions are interpreted differently across Member States, creating a regulatory patchwork: some national regulators apply the exemption narrowly and require frequent engagement with competent authorities; others have historically permitted broad use of the exemption for products that closely resemble commercially authorised products, creating market access conditions that bypass the centralised procedure. Developer and patient groups have raised concerns that the exemption can reduce the incentive to pursue full MA, since hospital-based production avoids the considerable cost and timeline of EMA assessment.

The 2023 pharmaceutical reform (provisional agreement reached 11 December 2025) is expected to address the hospital exemption, tightening the conditions and harmonising national reporting requirements. The reform also revisits the combined-product rules and the interface between the ATMP Regulation and the new Medical Device Regulations (EU) 2017/745 and 2017/746. The ATMP Regulation will be amended as part of this process. See the eu_pharmaceutical_legislation_reform knowledge guide for current reform status (as amended).