Regulation and access to advanced therapies: recent developments and future perspectives

Elisa Stefanini
Portolano Cavallo, Milan
estefanini@portolano.it

Claudio Todisco
Portolano Cavallo, Milan
ctodisco@portolano.it

Advanced therapies, also known as advanced therapy medicinal products (ATMPs), are innovative treatments or drugs that differ from traditional medications. Unlike conventional pharmaceuticals, which rely on chemically synthesised molecules, ATMPs are based on DNA or RNA, cells and tissues. Advanced therapies represent a relatively new sector in biomedicine, emerging from significant biotechnological progress made over the past 20 years. They provide new opportunities for diagnosing, preventing or treating severe diseases with limited or no therapeutic options, such as genetic disorders, chronic illnesses and cancer.

ATMPs can be categorised into four types:^[1]

• gene therapy medicinal products, aimed at treating diseases caused by defective genes;
• somatic cell therapy medicinal products, which use preparations containing cells or tissue to achieve therapeutic, diagnostic or preventive effects;
• tissue-engineered medicinal products, based on cells or tissues developed in laboratories to regenerate, repair or replace human tissue; and
• medicinal products for combined advanced therapies, incorporating one or more medical device as integral components of cell- or tissue-based drugs.

In order to address the particular nature of these therapies, they are subject to different set of rules, including those relating to the use of human tissues that represent raw materials for the manufacturing of ATMPs, as well as those relating to drugs.

Therefore, dealing with these products raises many challenges in regard to the potential interplay between such regulations and the need to adapt certain provisions concerning tissues and drugs to these very innovative therapies.

The regulation of advanced Therapies

From a regulatory perspective, ATMPs are considered full-fledged medicinal products, subject to the provisions set out in Directive 2001/83/EC concerning medicines for human use. However, due to their specific nature, advanced therapies benefit from tailored regulations that address their distinctive aspects, alongside general pharmaceutical rules.

Notably, Regulation (EC) 1394/2007 on advanced therapy medicinal products defines the various types of therapies and establishes specific rules for the authorisation, supervision and pharmacovigilance of ATMPs. It introduces additional provisions regarding summaries of product characteristics (SPCs), package leaflets, labelling and packaging (Chapter IV of the Regulation), which deviate from the general directives on pharmaceuticals. The Regulation also led to the establishment of the Committee for Advanced Therapies (CAT) within the European Medicines Agency (EMA). The CAT evaluates the quality, safety and efficacy data of all advanced therapy products submitted to the EMA. During the assessment process, the CAT drafts an opinion on the medicinal product’s attributes and submits it to the EMA’s Committee for Medicinal Products for Human Use (CHMP). The CHMP issues a recommendation, which influences whether the European Commission will authorise the product. The European Commission adopts its final decision based on the CHMP’s recommendation.

The authorisation of advanced therapies is centralised, as the European legislator deemed that these technologies require harmonised oversight. Products subject to the ‘medicines to be authorised by the Union’ designation (Regulation 726/2004, Annex I, laying down community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency) are granted a single licence valid across all the EU Member States. This licence includes the use of the trade name and multilingual documentation containing relevant information about the medicine. European-level authorisation allows Member State authorities to issue marketing permissions within their jurisdictions.

Specific rules have also been enacted for conducting clinical trials with ATMPs and ensuring good manufacturing practices for these therapies. In January, the EMA approved guidelines on the ‘quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials’, applicable from 1 July 2025.^[2] Additionally, manufacturing processes for advanced therapies have been addressed through good manufacturing practice (GMP) guidelines for advanced therapies,^[3] now included in volume 4 of the rules governing medicinal products in the EU, following consultations with the EMA, national regulatory authorities and stakeholders.

The tissue/cell regulation

From the Directive to the Regulation

As for the use of tissues and cells as starting materials for the manufacturing of ATMPs, the main reference is included in Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissue, as implemented in the EU Member States.

Although this Directive initiated the adoption of harmonised quality and safety standards, its very nature granted Member States a certain level of discretion in regard to their implementation, leading to significant differences in regulation across individual Member States and, consequently, to cross-border obstacles to sharing these substances. Furthermore, advances in science have also extended the use of additional substances in healthcare, which are not covered by the Directive and remain under Member State jurisdiction, exacerbating the issue of regulatory fragmentation.

These limitations of Directive 2004/23/EC led the European Commission to develop a proposal for a regulation that could be directly applied in all Member States, making the regulation of all substances used for human healthcare purposes more uniform.

The SoHO Regulation

Regulation (EU) 2024/1938, which is focused on quality and safety standards for substances of human origin (SoHO) intended for human application, published in July 2024, updated the existing regulatory framework. The Regulation aims to scale up the availability of such substances, promote cross-border circulation and enhance cooperation among public health authorities across EU Member States, ensuring uniform, high safety and quality levels for all SoHOs used in patient treatments.

Applicable from 2027, this Regulation replaces Directives 2002/98/EC and 2004/23/EC concerning blood, cells and tissues.

Key features of the SoHO Regulation include:

• the expansion of regulation to all human-origin substances (except solid organs for transplantation, which are dealt with by separate directives), beyond blood, tissues and cells, addressing analogous safety and quality concerns. Any future SoHO for patient application will automatically fall within the Regulation’s scope;
• the establishment of SoHO national authorities with authorisation, oversight and control functions;
• the introduction of authorisation systems for ‘SoHO preparations’ with specific clinical indications intended for human application or distribution;
• the distinction between ‘SoHO entities’ (subject to registration) and ‘SoHO centres’ (subject to authorisation), based on the nature of the activities involving substances;
• specific donor protection measures, including in relation to voluntary donation, the prohibition of incentives or financial benefits, aside from reimbursements, and informed consent protocols; and
• the creation of an EU platform for SoHOs, facilitating timely information exchange within the EU, such as on authorised SoHO preparations, registration status, SoHO centre authorisations and clinical study outcomes on SoHO use across the EU Member States.

Access to therapies

Access to ATMPs is significantly hindered by the diversity in pricing and reimbursement policies across the EU Member States. These therapies come at a high cost, due to their complexity and reliance on cutting-edge biotechnology. The inconsistency in how individual countries handle pricing and reimbursement exacerbates disparities in patient access.

Each EU Member State has its own healthcare funding structures and evaluation mechanisms, leading to stark differences in how ATMPs are priced and reimbursed. In wealthier countries with larger healthcare budgets, ATMPs are more readily integrated into reimbursement schemes, ensuring wider patient access. However, in countries with constrained resources, these therapies often remain out of reach, creating a fragmented landscape, wherein access depends on the patient’s geographic location rather than the medical need.

Furthermore, negotiations over pricing often take longer in some countries, due to budget limitations and complex approval processes. This leads to significant delays in making ATMPs available to patients. Furthermore, the lack of a harmonised EU approach to reimbursement decisions means that manufacturers must navigate multiple systems, increasing administrative burdens and costs, which may further restrict access in less affluent regions.

These issues have been effectively summarised in a white paper by the European Federation of Pharmaceutical Industries and Associations (EFPIA), entitled Shifting the Paradigm for ATMPs: Adapting Reimbursement and Value Frameworks to Improve Patient Access in Europe.^[4] The document proposes several recommendations to enhance access to ATMPs, including the adoption of outcomes-based innovative payment models and harmonisation of the evidence requirements across regulators and health technology assessment (HTA) agencies. Collaboration between industry, the EMA and HTA agencies is essential to align the relevant evidence standards and facilitate the acceptance of ATMP evidence, such as indirect treatment comparisons, surrogate endpoints and real-world evidence (RWE). This aligns with the objectives of the new EU regulation on health technology assessment, Regulation (EU) 2021/2282, and its implementing acts, notably the provisions for joint clinical assessments of ATMPs have been applicable since 12 January 2025.^[5]

Some highlights of the Italian regulatory framework

In Italy, the regulatory framework that governs the development of ATMPs is represented by the legislation on human tissues that implemented Directive 2004/23/EC and the following amendments (ie, Legislative Decree No. 191/2007 and some implementing decrees), together with Legislative Decree No. 219/2006 and the ATMPs Regulation.  However, many questions have arisen on how to handle the import/transport and use of human tissues for the specific purpose of manufacturing ATMPs. In the absence of a clear legislative indication, to support operators in this area, the Italian Ministry of Health issued a guideline in December 2022, clarifying that the application for clearance (nulla osta) in regard to the import/export of such materials can be filed with the competent Border Office of the Ministry of Health (Ufficio di Sanità Marittima, Aerea e di Frontiera or USMAF), as well as in regard to the ATMP’s manufacturer site (and not only in regard to tissue establishment).

In regard to the pricing and reimbursement procedures for ATMPs in Italy, they align with those applied to standard pharmaceutical products. However, access to innovative therapies is enhanced by a dedicated fund provided by the National Health System, aimed at supporting the reimbursement of drugs that demonstrate substantial therapeutic advancements compared to existing treatments, particularly those addressing unmet medical needs, as may be the case with advanced therapies. The recognition of a drug’s innovativeness and such subsequent access to dedicated funds are evaluated based on stringent criteria defined by the Italian Medicines Agency (Agenzia italiana del farmaco or AIFA), which are currently undergoing revisions.^[6]

In particular, the innovativeness of a product, traditionally granted based on the criteria set out in AIFA Resolution No. 1535/2017 (ie, therapeutic need, added therapeutic value, quality of evidence), is set to be evaluated according to new parameters. These updated criteria will encompass the technology employed in the production of the active ingredient, the mechanism of action, the method of administration to the patient, the clinical efficacy and safety, the impact on the patient’s quality of life and the implications for the organisation of healthcare services. An open consultation is currently being conducted by the AIFA, with all interested stakeholders.^[7] Upon its conclusion, the resolution outlining the new criteria for evaluating innovativeness is expected to be adopted.

For the year 2025, the fund’s allocation for innovative drugs amounts to €900m. By bridging the gap between cutting-edge drug development and patient accessibility, the fund represents a pivotal example of how strategic healthcare policies can address systemic challenges and improve public health outcomes.

Notes