Clinical trials for ATMPs

1. Legal challenge

Clinical regulation in the EU was governed by the Directive 2001/20/EC relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use. But the lack of homogeneity in the implementation of the directive within Member States appeared to be a burden on European research. 

The way clinical trials are conducted in the EU undergoes a major change since the Regulation (EU) No 536/2014 came into application on 31 January 2022. The Regulation harmonises the assessment and supervision processes for clinical trials throughout the EU, via the CTIS. CTIS almost fully replaces the EudraCT database, the use of the latter being widely limited now. The EMA sets up and maintains this CTIS, in collaboration with the Member States and the European Commission.

Before the Clinical Trial Regulation fully came into force, a three-year transitional period, from 31 January 2022 to 31 January 2025, was arranged during which clinical trial authorisations issued in accordance with Directive 2001/20/EC remained in force. 

The move from a Directive to a Regulation is legally significant as it replaces some divergent national transpositions with directly applicable, and uniform rules across all Member States. This aims to reduce legal uncertainty for clinical trials actors, especially sponsors in multi‑state trials, and to streamline interactions with NCAs and ethics committees through a single electronic portal entry point. The practical implementation of the Clinical Trials Regulation and CTIS has brought challenges for all stakeholders including adapting national procedures, developing new internal processes, IT systems, and ensuring that responsibilities between NCAs and ethics bodies are clearly defined and consistently applied.

Moreover, the conduct of clinical trials for ATMPs must comply not only with the Clinical Trials Regulation (EU) No 536/2014, but also with the broader regulatory framework applicable to ATMPs, including Regulation (EC) No 1394/2007 and the general pharmaceutical requirements laid down in Directive 2001/83/EC, currently undergoing reform (See section below). Consequently, sponsors must simultaneously address requirements relating to clinical trial authorisation, GCP, manufacturing standards (GMP), and the quality, non-clinical and clinical data requirements specific to investigational ATMPs. 

Sponsors and investigators must therefore navigate not only new procedural requirements in CTIS, but also evolving guidance and expectations regarding the legal content and level of detail needed in applications for ATMP trials. In this context, continuous dialogue between regulators, ethics committees and developers, as well as targeted guidance and capacity‑building initiatives at EU level, are essential to ensure that the new legal framework effectively facilitates high‑quality clinical research while maintaining a high level of protection for trial subjects.
 

2. Ethical challenge

The conduct of a clinical trial involves several risks related to the experimental nature of medical research. One of the main ethical challenges is to find the balance between those risks to subjects and the expected benefits produced by the research. The general principle which is legally established is: “A clinical trial may be conducted only if:

     (a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests; and

     (b) it is designed to generate reliable and robust data.”

(Article 3 of Regulation (EU) No 536/2014)

These principles are particularly critical in the context of clinical trials for ATMPs as the interventions are often irreversible, long-lasting and associated with significant scientific uncertainty regarding both their efficacy and their long‑term safety profile. In such trials, careful risk–benefit assessment, robust preclinical data, and independent scientific and ethical review are essential to explain and justify exposing participants to ATMPs. Ensuring truly informed consent can also be challenging as patients may have severe or lifethreatening conditions with limited treatment options and may therefore be especially vulnerable to therapeutic misconception or overestimate the potential benefits of an advanced therapy. Additional safeguards are thus required, including transparent communication about uncertainties, long-term follow-up plans, and the involvement of patients representatives and specialised ethics expertise in the trial design and review process.
 

3. Economical and societal challenge

In medical research, it is well-known that developing and obtaining a marketing authorisation for a medicinal product is a very long and expensive process in general, and even more when it comes to ATMPs. See Standard Centralised Procedure for ATMPs | EuroGCT. Indeed, the previous lack of harmonisation in clinical trials national regulations and processes, which is now addressed by Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, raised the issue of the European competitiveness in medical research, especially concerning the unavoidable step of clinical trials. Moreover, European competitiveness in this field is not only an economical challenge but also a public health one. In fact, early access to medical innovations for European citizens also depends on researchers’ ability to perform clinical trials in EU countries.

In the case of ATMPs, the economic aspect is even more pronounced due to complex manufacturing processes, high development costs, and sometimes small target populations, which can hinder investment and limit the number of trials initiated in Europe. These factors risk widening the gap between innovative therapies developed outside the EU and the availability of such treatments for European patients. Harmonised regulatory frameworks such as Regulation (EU) No 536/2014 together with the ACT-EU (an initiative to accelerate clinical trials in the EU), therefore aim not only to reduce administrative and financial barriers but also to ensure that EU remains an attractive and competitive environment for clinical research in advanced therapies, ultimately supporting both economic growth and equitable public‑health outcomes.
 

4. Scientific challenge

ATMPs, because of the specific risks they pose, are subject to stricter rules than classical medicines to ensure patient protection. From a scientific and technical perspective, the characterisation and manipulation of living cells and tissues for therapeutic use is problematic in terms of ensuring their long-term stability, particularly concerning their often targeted capacity to evolve and interact within the human body.

This leads to difficulties in ensuring the long-term safety and efficacy of these ATMPs, whether it is the risk of tumors, contamination of cells and tissues with infectious agents or immune rejection, or, in the case of gene therapies, the integration of genetic material in an unintended location. These difficulties have to be taken into account within the design of clinical trials of ATMPs, which is challenging as specific to each ATMP.

From a clinical trial perspective, these scientific difficulties mean that conventional trial designs are often insufficient for ATMPs. Indeed, trial designs must be highly tailored to the specific medicine, mechanism of action, route of administration and target population, with careful consideration of dosing regimens, patient selection and long‑term follow‑up strategies. Close collaboration between researchers, regulators and ethics committees are essential to define appropriate endpoints, safety monitoring plans and benefit-risk evaluation frameworks. This makes the scientific design of ATMP trials inherently more complex and resource‑intensive than for classical medicines, but also underlines the need for flexible, science‑driven regulatory approaches that safeguard patients while enabling innovation to progress.

1. ACT-EU: ACT-EU was created by a joint action from the EMA, the Heads of Medicines Agency (HMA) and the European Commission (DG SANTE and DG RTD). It was established in January 2022 with the impulse of the implementation of the new Clinical Trials Regulation. ACT-EU has a workplan with 11 priority areas aimed at enhancing the efficiency and effectiveness of clinical trials across the EU. The ACT-EU workplan 2025 – 2026 explains clearly the aim of this action is to accelerate Clinical Trials in the EU by supporting smarter clinical trials using multiple processes (innovation, regulatory and technological) to foster innovation. “The vision is to have better, faster and optimised clinical trials, benefitting patients and healthcare in Europe. Seamless coordination between stakeholders, regulators and ethics committees strengthens cross-border collaboration. The ACT-EU multi-stakeholder platform is central to this”.

ACT-EU translates this vision into a set of concrete projects that directly impact the planning and conduct of clinical trials. Priority areas include improving the use of CTIS, streamlining assessment procedures between NCAs and ethics committees, promoting innovative trial designs such as platform, adaptive or decentralised trials, and strengthening methodological and regulatory guidance for complex studies. The initiative also focuses on capacity building for regulators and stakeholders, enhanced transparency and use of real world data, and better integration of patient perspectives into trial design and governance. For sponsors and investigators, ACT-EU should progressively lead to more predictable timelines, clearer expectations across Member States and a more supportive environment for high quality, patient centred clinical research in the EU.

Find out more about ACT-EU on their website and also read the workplan for 2023-2026, and the latest yearly workplan for 2025-2026. 
 

2. Clinical Trials Coordination Group (CTCG): The CTCG is a working group at the Heads of Medicines Agencies (HMA). It is composed of experts from national medicines agencies on the assessment and oversight of clinical trials. This group aims at enhancing the attractiveness of EU/EEA for clinical trials by promoting harmonization and optimization of regulations.

The CTCG develops common guidance, Q&A documents and best‑practice papers to support consistent implementation of the EU Clinical Trials Regulation across Member States. It works to align national approaches on key topics such as assessment of complex or multinational trials, use of CTIS, safety reporting, substantial modifications and transparency rules.

In addition, the CTCG serves as a forum where NCAs can discuss challenging or novel trial designs, share inspection and oversight experience, and coordinate positions on emerging scientific or regulatory issues. By doing so, it complements the work of EMA committees and working parties and provides sponsors with clearer, more predictable and harmonised regulatory expectations when planning and conducting multi‑country clinical trials in the EU/EEA.

Find out more about this group here. To read the CTCG mandate follow this link.
 

3. Pharmaceutical reform: The ongoing reform of the EU’s pharmaceutical legislation, commonly referred to as the “EU Pharmaceutical Package” including both the compromise text of a Regulation and the compromise text of a Directive, initiated in April 2023 and the subsequent political agreement reached on the 11 December 2025, is expected to introduce several regulatory changes that may affect the conduct of clinical trials involving ATMPs. One of the key objectives of the reform, as stated in Recitals 3 and 4 of the compromise text of a Regulation, is to strengthen the EU’s capacity to foster innovation while ensuring timely access to safe and effective medicines for patients across all Member States. The legislative proposals aim to simplify and modernise the regulatory environment governing pharmaceutical research, including clinical development processes. In particular, the reform seeks to reduce administrative burdens and streamline regulatory procedures, thereby making the EU a more attractive environment for clinical research.

The following proposals can be underlined:

a. While Regulation (EU) No 536/2014 provides a harmonised procedural framework for clinical trials, the compromise text of a Directive reshapes the incentives surrounding clinical development. In particular, Articles 81 and 82 of the compromise text of a Directive, read in light of Recital 60, establish a system of modulated regulatory data protection and market protection. These provisions allow for additional periods of protection where medicinal products address unmet medical needs or contribute to public health objectives. Although they do not directly regulate clinical trials, they create incentives for sponsors to generate robust clinical evidence, thereby indirectly influencing trial design, data validity criteria and development strategies.

b. Beyond these direct and incentive-based effects, the pharmaceutical reform significantly impacts the clinical trial ecosystem through the reorganisation of scientific evaluation and regulatory support mechanisms regarding:

• The restructuring of scientific committees, as reflected in Recital 37 of the compromise text of a Regulation, which addresses the integration of expertise previously concentrated within the Committee for Advanced Therapies into broader EMA structures such as the CHMP to contribute to a more streamlined and integrated scientific assessment. While this move does not directly regulate clinical trials, it affects the evaluation of clinical data generated during such trials, thereby influencing expectations regarding evidence generation, particularly for complex products such as ATMPs;
   

• Scientific advice: The strengthening of EMA scientific advice plays a central role in supporting the marketing authorisation application of ATMP, including the shaping of their clinical development.

  The EU Pharmaceutical Package establishes an incentive architecture linking clinical trial design to regulatory market protection. Under the compromise text of a Directive, a twelve-month prolongation of the regulatory market protection period is subject to whether the clinical trials supporting the marketing authorisation application use a relevant and evidence-based comparator in accordance with scientific advice provided by the EMA (Articles 81.2(b) and (c)), and/or whether the clinical trials evaluating the efficacy of the medicinal product and used for the marketing authorisation were conducted in more than one Member State (Articles 81.2(c) and (d)). Compliance, or justified non-compliance, with an EMA scientific advice has therefore tangible consequences for market exclusivity. Article 81.3 further mandates the EMA to develop scientific guidelines on comparator selection.

  These incentives on comparative clinical evidence aim both to strengthen regulatory assessment and to generate data capable of supporting downstream health technology assessments and decisions on pricing and reimbursement (Recitals 52 and 52(a) of the compromise text of a Directive). The EMA and NCAs should actively support the design of comparative trials when providing pre-authorisation advice (Recital 52a of the compromise text of a Directive).

  In addition, the EMA is enabled to consult various experts and authorities when needed in preparing scientific advice, including on clinical trials aspects:

  • Member State clinical trial experts (Article 58.2 of the compromise text of a Regulation).
  • Relevant NCAs and bodies for the exchange of information on general issues of scientific or technical nature (Article 162.1 of the compromise text of a Regulation). This process expressly covers guidelines on clinical trial design and evidence generation across the medicine lifecycle. It encompasses:
    • HTA bodies and pricing and reimbursement authorities with the aim that such dialogue serves to align pre-authorisation regulatory guidance with the broader evidence needs of downstream decision-makers. (Recitals 38 and 39 of the compromise text of a Directive)
    • Authorities or public bodies established under other relevant EU legal acts, including experts in clinical trials, medical devices, or substances of human origin, as required for the scientific advice in question. (Recital 65 of the compromise text of a Regulation). Recitals 45 and 45(a) also highlight the need for submission of raw clinical trial data and attention to trial composition, including gender-based equity.

  The EMA's scientific advice function therefore forms part of a multi-authorities and experts consultation process that goes far beyond the simple one regulator- one sponsor relationship. The importance of early regulatory interaction and support mechanisms for medicines reinforce a model in which clinical development is guided through iterative dialogue with regulatory authorities. More information on scientific advice on EuroGCT Support from several competent authorities for the development of innovative medicines.

• Regulatory sandboxes: The compromise text of a Regulation introduces a regulatory sandbox mechanism with direct implications for clinical research. Under Article 113.2, a sandbox establishes a controlled regulatory framework allowing targeted adaptations to certain requirements of the EU legislation to the extent strictly necessary to assess whether a marketing authorisation can be granted for the concerned medicine. With this process, the core principles of quality, safety and efficacy must be maintained, and the sandbox operates under the direct supervision of the competent authorities of the Member States concerned. The clinical trial dimension is addressed in Article 114.1 which provides that Member States shall take the sandbox plan into consideration when authorising a clinical trial application for products covered by a sandbox. 

  The sandbox under Recital 135 is a time-limited experimentation space designed to generate regulatory learning while preserving accountability. The supervisory powers of competent authorities and the liability of participants, including clinical trial sponsors, remain fully in force throughout the process. The sandbox outcomes are expressly envisaged as a source of input for future legislative evolution as the Commission is empowered to develop adapted regulatory frameworks on the basis of sandbox results. The sandbox thus operates as a structured pathway for evidence-based regulatory adaptation, enabling the testing of innovative medicines or regulatory approaches within a controlled environment under regulatory supervision.

• Clinical trials involving Genetically Modified 0rganisms (GMO)-based medicines: The Pharmaceutical Package also addresses a long-standing regulatory bottleneck affecting clinical trials with investigational medicines containing or consisting of GMOs. Recitals 145 to 152 of the compromise text of a Regulation acknowledge that the current framework, which requires sponsors to comply with divergent national procedures under Directives 2001/18/EC and 2009/41/EC, generates significant delays  particularly for multi-centre trials. The Regulation therefore amends Regulation (EU) No 536/2014 to establish a centralised Environmental Risk Assessment (ERA) procedure, coordinated by a Reporting Member State and supported where relevant by the EMA's Environmental Risk Assessment working party. More information on Genetically Modified Organisms-Based Advanced Therapy Medicinal Products | EuroGCT.
   

• Paediatric clinical trials: The compromise text of a Regulation also reinforces the framework governing clinical trials in the paediatric population. Recital 106 precises that medicines, before to be marketed within the EU, must be studied in children to ensure they are appropriately authorised for paediatric use and presented in suitable dosages and formulations. Recital 110 preserves a proportionate approach: the obligation to conduct paediatric studies may be waived where the medicine is likely to be ineffective or unsafe for children, where it offers no significant therapeutic benefit over existing options, or where the disease concerned occurs only in adult populations. The obligation is maintained where the product's mechanism of action is relevant to a different paediatric condition within the same therapeutic area.

  On the transparency side, Recitals 122 and 123 and Article 94 of the compromise text of a Regulation, introduce enhanced reporting obligations for paediatric clinical trials conducted in third countries. Where such trials are referenced in an agreed paediatric investigation plan, their key elements, i.e. trial protocol, investigational medicines, therapeutic indications and trial population, must be registered in the EU clinical trials database prior to the start of the trial, and a summary of results made publicly available within six months of completion, extendable to twelve months for justified scientific reasons. Article 177.4 of compromise text of a Regulation also amends Regulation (EU) No. 536/2014 directly, inserting into Article 37.4 a specific six-month deadline for the submission of results summaries to the EU database in all clinical trials involving medicines in the paediatric population. These provisions collectively strengthen the transparency framework of paediatric clinical development, reinforcing the obligation to generate and disclose robust data on medicines, including ATMPs, for children.

• Clinical trials conducted in third countries: The compromise text of a Regulation also consolidates the conditions under which clinical trials conducted outside the EU may support a centralised marketing authorisation application. Recital 52 states that where clinical trials have been carried out in third countries on medicines intended for a centralised marketing authorisation, it must be verified, at the time of the marketing authorisation evaluation, that those trials were conducted in accordance with principles equivalent to those of Regulation (EU) No. 536/2014. This verification covers both the rights and safety of participants and the reliability and robustness of the data generated in the clinical trial. This requirement is stated in Article 6.1 which requires that marketing authorisation applications include an explicit declaration confirming that clinical trials carried out outside the Union meet the ethical requirements of Regulation (EU) No. 536/2014. Article 94(4) further empowers the Commission to adopt implementing acts to refine, on the basis of operational experience, the details to be submitted to the EU database concerning third-country trials.

  These provisions ensure that clinical data generated outside the EU is subject to consistent ethical and transparency standards as a condition of regulatory acceptance within the EU.

• Processing personal data: Under Article 169.1 of the compromise text of a Regulation, the EMA is empowered to process personal health data from clinical trials and other sources including real-world data for the purpose of improving the robustness of its scientific assessment or verifying claims of the applicant or marketing authorisation holder. This power also extends to broader regulatory science activities, provided that two cumulative conditions are met: the processing must be strictly necessary and proportionate to the objectives pursued, and where sensitive health data are involved, appropriate technical and organisational safeguards must be in place to protect data subjects' rights in line with EU law.

  Overall, while the precise implementation details will depend on the final legislative text and subsequent regulatory guidance, the EU Pharmaceutical Package does not fundamentally alter the legal framework governing the conduct of clinical trials, which remains governed by Regulation (EU) No 536/2014. However, it provides for some changes. Through a combination of incentive mechanisms, enhanced scientific guidance and innovation-support tools such as regulatory sandboxes, the reform is likely to promote more robust, strategically designed and regulatorily aligned clinical trials across the EU. See also the impact of the pharmaceutical reform on the clinical trials of GMO-based ATMP, on EuroGCT Genetically Modified Organisms-Based Advanced Therapy Medicinal Products.
   

4. It currently exists specific rules concerning clinical trials of advanced therapy investigational medicinal products. They provide supplementary delays in order to consult experts for the assessment of the scientific part of clinical trials applications in view of ATMPs’ specificities:

a. For the assessment of initial clinical trials applications: The reporting Member State may extend the 45 days period to submit the final Part I of the assessment report to the sponsor and the other Member State by a further 50 days for clinical trials involving an advanced therapy investigational medicinal product  for the purpose of consulting with experts. (Article 6§7 of Regulation (EU) No 536/2014).

The proposal of the European Biotech Act provides for a complete rewriting of the Article 6, with a significant reduction of timelines, including the deletion of this additional delay. (See below the Biotech Act section)

b. For the assessment of a substantial modification of an aspect covered by the scientific part of the assessment report: The reporting Member State may extend the 38 days period to submit, through the EU portal, the final assessment report including its conclusion to the sponsor and the other Member states concerned by a further 50 days for clinical trials involving an advanced therapy investigational medicinal product for the purpose of consulting with experts. (Article 18§5 of Regulation (EU) No 536/2014).

The proposal of the European Biotech Act provides for the deletion of this additional delay to reduce the clinical trial timelines. (See below the Biotech Act section)
 

5. Proposal for a new European Biotech Act:

The proposal for a new European Biotech Act is also proposing changes regarding clinical trials of ATMPs. The European Commission formally proposed the EU Biotech Act on 16 December 2025, following a public consultation held earlier that year. The legislation now enters the inter-institutional negotiation phase between the European Parliament and the Council, with final adoption anticipated in late 2026 or 2027. Consequently, entry into application is projected for the 2027–2028 period at the earliest.

The proposal introduces a targeted reform of the Clinical Trials Regulation (EU) No 536/2014, with significant implications for ATMP clinical trials. Its objective is to “simplify and future-proof the regulatory environment” and reduce time-to-market for innovative therapies, particularly in biotechnology and health. (Biotechnology - Public Health - European Commission).

The key amendments to Regulation (EU) No 536/2014, provided by Article 58 of the proposal for European Biotech Act, are the following:

a. Authorisation timelines for ATMP clinical trials: previously, certain additional assessment periods (+ 50 days) applied specifically to ATMPs, which lengthened the overall evaluation process. Under the Biotech Act, Article 6 of the Regulation (EU) No 536/2014 is amended to remove this additional period, thereby aligning the assessment of ATMP trials with standard timelines applicable to other clinical trials. This change is expected to reduce procedural delays for multinational ATMP studies and to accelerate the pace of clinical development.

b. Reduction of overall authorisation timelines by amending Articles 5 to 8 of the Regulation (EU) No 536/2014. These changes restructure the coordinated assessment procedure, shorten statutory decision deadlines, and limit delays associated with the review of substantial modifications. For instance, the maximum assessment period for multinational trials is reduced from 106 days to 75 days, while deadlines for reviewing protocol amendments are shortened from 96 to 47 days or from 64 to 33 days depending on the nature of the modification. These measures are designed to facilitate more efficient trial initiation and continuation, which is particularly relevant for the complex and iterative development of ATMPs.

c. The strengthening of the role of the reporting Member State by amending Articles 5 and 7 of the Regulation (EU) No 536/2014. By clarifying and enhancing the reporting Member State’s coordination responsibilities, the amendments aim to harmonise scientific and ethical evaluations across Member States. This is especially important for ATMP trials, where divergent national interpretations could otherwise create bottlenecks in multinational studies.

d. Facilitation of the use of previously submitted clinical trial data through an amendment to Article 11 of the Regulation (EU) No 536/2014. This provision enables sponsors to reference existing data for investigational products in related clinical trials, thereby reducing duplicative submissions and allowing for more efficient iterative development. This is particularly relevant for ATMPs, where repeated preclinical and early-phase clinical data may serve as a basis for successive trials in the development pathway.

e. Establishment of regulatory sandboxes to provide experimental frameworks in which ATMPs can be developed under controlled regulatory flexibility. They aim to support innovative clinical trial protocols, including combination therapies and novel manufacturing processes, while safeguarding patient safety and data integrity.

f. The European Biotech Act states also that “Communication between sponsors and Member States will be improved during assessments. A single, core dossier for investigational products will simplify clinical trials using the same investigational medicine and help the conduct of registration trials and the preparation of marketing authorisation applications in Europe. Simplifications for low-intervention clinical trials will be further supported by introducing a new category of ‘minimal-intervention’ clinical trials. Mandatory EU harmonised templates will enable harmonisation. A single assessment process will be defined for combined studies involving the investigation of a medicine together with a medical device or an in-vitro diagnostic. The legal basis for processing personal data in clinical trials in accordance with Regulation (EU) 2016/679 requirements will be harmonised. Accelerated and simplified procedures will enable multinational clinical trials to be carried out on in relation to public health emergencies”. (Amendments to Regulation (EU) No 536/2014 (Clinical Trials Regulation)

For an overview of the key amendments to Regulation (EU) No 536/2014, provided by Article 58 of the proposal for European Biotech Act, please see below an extract from a EuroGCT poster presented at ISCT 2026: A. MAHALATCHIMY, V. ROBY, C. CHABANNON, The European Commission proposal for a new regulation on biotechnology: why does it matter for ATMP? , ISCT 2026, 6-9 May 2026, Dublin, Ireland.

See also the impact of the European Biotech Act on the clinical trials of GMO-based ATMP, on EuroGCT Genetically Modified Organisms-Based Advanced Therapy Medicinal Products.

See also the European Commission’s Factsheet - How Clinical Trials will change under the Biotech Proposal.

In conclusion, the European Biotech Act represents a transformative set of reforms for ATMPs clinical trials in the EU in particular by removing ATMP-specific procedural extensions and reducing overall timelines. The Act creates a more predictable and innovation-friendly environment to accelerate the development of advanced therapies while maintaining high standards of patient safety, scientific requirements, and regulatory transparency.

See also the impact of the European Biotech Act on the clinical trials of GMO-based ATMP, on EuroGCT Genetically Modified Organisms-Based Advanced Therapy Medicinal Products.

See also the European Commission’s Factsheet - How Clinical Trials will change under the Biotech Proposal.

In conclusion, the European Biotech Act represents a transformative set of reforms for ATMPs clinical trials in the EU in particular by removing ATMP-specific procedural extensions and reducing overall timelines. The Act creates a more predictable and innovation-friendly environment to accelerate the development of advanced therapies while maintaining high standards of patient safety, scientific requirements, and regulatory transparency.

Interactions with National Competent Authorities (NCAs)

NCAs hold primary responsibility for authorising or not clinical trials in their Member States. The NCAs' assessment of applications for clinical trial authorisations covers especially the safety and quality of the products used in the trial as well as the safety of the people participating in the research. 

Through the CTIS, NCAs assess applications for compliance with scientific, ethical, quality, and safety standards, focusing on the investigational medicinal product, trial design, risk-benefit ratio, and participant protection measures.

NCAs provide ongoing supervision throughout the trial lifecycle: sponsors must report substantial modifications, urgent safety measures, serious adverse events, any fact likely to compromise the safety of the participants, and annual safety reports via the CTIS. In cases of safety concerns, NCAs can mandate protocol amendments, suspend new inclusions, impose additional participant safeguards, or even ban the trial.

The NCAs also inspect the sites where clinical trials are carried out (health establishments, authorised research sites, etc.), sponsors of this research or the subcontractors of these sponsors, CROs, and laboratories. These inspections cover notably the safety and rights of persons participating in trials. Non-compliance may trigger corrective or preventive actions, trial holds, or regulatory sanctions. In case of multinational clinical trials, a reporting Member State coordinates the assessment with other concerned Member States providing input within strict timelines. This coordinated validation ensures harmonised standards while respecting national competencies for site-specific authorisation and inspection.

More information on the interactions with NCAs: Support from National medicines Agencies for the development of innovative medicines at the National levels | EuroGCT
 

Participation of ethics committees

Ethics Committee provides independent ethical review of clinical trial protocols to safeguard participant rights, safety, dignity, and well-being. Ethics Committees are usually established by a government or an institutional charter (hospital, research institute, university, etc.) and include healthcare professionals, methodologists, patients and lay representatives, and legal and statistical experts. The ethics committee assesses the ethical admissibility of a research project before participants can be recruited into a study. It also verifies vulnerable population protections. The ethics committee also examines certain financial and scientific aspects of the project as long as they raise ethical questions. The establishment, legal status and functioning of ethics committees vary from a Member State to another. 

Ethics committees help to ensure the welfare, safety and protection of those involved in research. To this end, an ethical assessment and a favourable opinion are required before the study begins; once the study has started, it will be monitored continuously.

Through the CTIS coordinated procedure, sponsors submit the protocol dossier simultaneously to the lead Member State's NCA and relevant ethics committees, simplifying the submission procedure. Ongoing supervision by the ethics committees includes review of substantial modifications impacting participant safety, integrity, or scientific value.
 

Scientific advice relating to the clinical trial or the investigational medicinal product

Medicine developers can ask the EMA for scientific advice and protocol assistance at any stage of a medicine’s development in order to know the most appropriate methods and study designs to generate robust evidence on a medicine’s benefits and risks, including the design of pivotal clinical trials. Scientific advice and protocol assistance are formally issued by the CHMP on the recommendation of the Scientific Advice Working Party. 

The EMA recommends its scientific advice and protocol assistance for medicine’s developers when: “

• they are developing innovative medicine and there appears to be no or insufficient relevant detail in EU guidelines or guidance documents, or in Pharmacopeia monographs, including draft documents or monographs released for consultation;
• the developer chooses to deviate from scientific guidelines in its development plan;
• the medicine developer has limited knowledge about medicine regulation, such as some academic groups or micro, small and medium sized enterprises (SMEs).”

Scientific advice and protocol assistance can be asked during the initial development of a medicine before submission of a marketing authorisation application (e.g. on Phase I–III trial design, endpoints, comparators, statistics) but also later on, during the post-authorisation phase towards further development. The scientific advice or protocol assistance request is made through the IRIS platform.

Apart from scientific advice and protocol assistance, it exists several support tools for innovative medicines’ development at the EMA level (See EuroGCT Support for innovative medicines’ development at the EMA level) and mechanisms that are specific to ATMP (see EuroGCT Support specific to ATMP's development at EMA level).

Scientific advice on clinical development programmes and individual trial designs can also be delivered at national level by national medicines agencies. (See EuroGCT Support from National medicines Agencies for the development of innovative medicines at the National levels).

Finally, it also exists support tools to interact with several competent authorities (See EuroGCT Support from several competent authorities for the development of innovative medicines | EuroGCT)
 

Participation of EMA

Apart from scientific advice and protocol assistance, the EMA plays a key role in medicines development in the EU and in supporting clinical trials across the EU.

The EMA contributes to protect clinical trials subjects by coordinating Good Clinical Practice (GCP) compliance with Member States’ competent authorities. It develops GCP guidance, organises joint GCP inspections of sponsors, CROs and trial sites for multi-state trials, and facilitates harmonised GCP enforcement through the CTCG and GCP Inspectors Working Party. While individual Member States retain primary inspection authority under the Clinical Trials Regulation, EMA ensures consistent standards and can trigger inspections based on CTIS safety signals or marketing authorisation assessments.

The CTIS is the single EU/EEA portal and database for the submission, assessment and supervision of clinical trials under the EU Clinical Trials Regulation. It replaces the previous fragmented system organised with national submissions plus part of the EudraCT database with one harmonised electronic workflow. Through CTIS, sponsors submit a single dossier per trial, which is then assessed in a coordinated way by Member States, and use the same platform for substantial modifications, safety reporting obligations specific to the EU Regulation, and trial end notifications. This centralisation strengthens consistency of regulatory decisions, reduces administrative burden, and improves oversight across the trial life‑cycle.

The EMA plays a pivotal role in the CTIS serving as the primary technical and scientific partner to the European Commission. EMA led the functional specification design and stakeholder consultations. It handles system maintenance, sponsor workspace management, coordinated multi-state assessments, and continuous improvements based on user feedback from regulators, ethics committees, and industry.

Key information entered into CTIS is made publicly accessible, subject to protection of personal data and commercially confidential information, including trial registration details, summary results and, where required, lay summaries written in non‑technical language. Sponsors must therefore plan from the outset for timely disclosure of core protocol characteristics and main findings, and for the preparation of clear lay summaries that can be understood by patients and the general public. This transparency policy aims to facilitate secondary use of data and support informed decision‑making by clinicians and patients.

EMA's CTIS support also includes training resources, Q&A guidance, and SME simplification measures, making it the central hub for regulatory dialogue and oversight across the EU/EEA.

More information on the CTIS on the EMA website here and here.

EMA’s CHMP is then responsible for conducting the scientific assessment of human medicine for which an EU-wide marketing authorisation is sought through the centralised procedure. See for more information Standard Marketing Authorisation Pathway: Centralised Procedure for ATMPs | EuroGCT.

As part of this work, the CHMP reviews the clinical trial data included in the marketing authorisation application alongside non-clinical, quality, and risk management data to determine whether the medicine meets EU standards for quality, safety, and efficacy. The CHMP issues a positive or negative opinion, which forms the basis of the European Commission's final decision on marketing authorisation.

This section sets out the main practical steps governing the life‑cycle of a clinical trial under Regulation (EU) No 536/2014. It should be noticed that some of the following provisions might be modified when The proposal of the European Biotech Act will be adopted and enforced.
 

1. The Prior authorisation (Regulation (EU) No 536/2014 – Chapter II – Article 4)

Every clinical trial must be subject to prior authorisation before to start. This prior authorisation encompasses scientific and ethical reviews of the clinical trial application. The scientific review is performed by one or several National Medicines Agencies depending on where the clinical trials will take place. The ethical review of the clinical trial must be performed by each ethics committee of the Member State concerned.
 

2. Submission of the application dossier (Regulation (EU) No 536/2014 – Chapter II – Article 5)

In order to obtain an authorisation, the clinical trial’s sponsor must submit an application dossier (see: Practical Steps - Application dossier) to the intended Member States concerned through the EU portal (CTIS), and propose a Member State concerned as reporting Member State for multi-national clinical trials. 
 

3. The application dossier for initial application (Regulation (EU) No 536/2014 –Annex I) 

“The application dossier for the authorisation of a clinical trial shall contain all required documentation and information necessary for the validation and assessment […] relating to:

     (a) the conduct of the clinical trial, including the scientific context and arrangements taken,
     (b) the sponsor, investigators, potential subjects, subjects, and clinical trial sites;
     (c) the medicinal products and, where necessary, the auxiliary medicinal products, in particular their properties, labelling, manufacturing and control
     (d) measures to protect subjects;
     (e) justification as to why the clinical trial is a low-intervention clinical trial, in cases where this is claimed by the sponsor”.

(Article 25.1. of Regulation (EU) No 536/2014)

The list of required documentation and information for initial application is set out in Annex I of the Regulation (EU) No 536/2014). It includes a cover letter with EU CT number, a proof of payment of fee, Statement of compliance with Regulation (EU) 2016/679 (GDPR), a section on Part I and a Section on Part II.

Section on Part I includes the protocol, the investigator brochure, the documentation relating to compliance with good manufacturing practice (GMP) (see: Good Manufacturing Practice entry), the Investigational Medicinal Product Dossier, the Auxiliary Medicinal Product Dossier, information on scientific advice and paediatric investigational plan (PIP), information on Labelling.

Section on Part II has to comply with language and National requirements per each Member State concerned. It covers information on: Recruitment arrangement; Subject information sheet, informed consent form, other subject information material; Suitability investigator; Suitability facilities; Proof of Insurance or indemnification; Financial and other arrangements; Compliance with national requirements on data protection; and Compliance with use of biological samples.

Regarding Compliance with use of biological samples, the EU Clinical Trials Expert Group developed a template for Part II of the application dossier in order to comply with the Regulation (EU) No 536/2014 on Clinical Trials. Although it is not mandatory to use this template, it can be particularly useful to sponsors.

New template - Compliance with applicable rules for biological samples– 1st February 2022: 

“This form may be used by Sponsors of clinical trials in Part II application dossier to provide information about ‘compliance with the applicable rules for the collection, storage and future use of biological samples form clinical trials subjects’ (Regulation (EU) No 536/2014, Article 7.1 (h)). This is not a mandatory form and different national arrangements may be in place, which should be confirmed prior to submission”.
 

4. Substantial modification of a clinical trial (Regulation (EU) No 536/2014 – Chapter III, Article 15)

“A substantial modification, including the addition of a clinical trial site or the change of a principal investigator in the clinical trial site, may only be implemented if it has been approved in accordance with the procedure set out in this Chapter” (See below: Practical Steps – Application dossier for the authorisation of substantial modifications).
 

5. The application dossier for substantial modification on a clinical trial (Regulation (EU) No 536/2014 – Annexe II)

“The application dossier for the authorisation of a substantial modification shall contain all required documentation and information necessary for the validation and assessment referred to in Chapter III of the Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use:

 a) a reference to the clinical trial or clinical trials which are substantially modified using the EU trial number referred to in the third subparagraph of Article 81(1) (the ‘EU trial number’);

b) a clear description of the substantial modification, in particular, the nature of and the reasons for substantial modification;

c) a presentation of data and additional information in support of the substantial modification, where necessary;

d)  a clear description of the consequences of the substantial modification as regards the rights and safety of the subject and the reliability and robustness of the data generated in the clinical trial.”

(Article 25.2. Regulation (EU) No 536/2014)

The list of required documentation and information for a substantial modification of a clinical trial is set out in Annex II of the Regulation (EU) No 536/2014). It includes a cover letter, a modification application form, a description of the modification, additional supporting information, an update of the EU application form, and a proof of payment of fee (information par Member State concerned).
 

6. Procedure for the initial authorisation of a clinical trial

The procedure for the initial authorisation of a clinical trial includes 3 phases

• The validation phase explained in Regulation (EU) No 536/2014 – Chapter II – Article 5.
• The assessment phase explained in Articles 6 (Part I) and 7 (Part II) of Regulation (EU) No 536/2014.
• The decision phase explained in Article 8 of Regulation (EU) No 536/2014.

See below the calendar for the initial authorisation of a clinical trial as provided by the Clinical Trials Coordination and Advisory Group, Clinical Trials Regulation (EU) No 536/2014 in practice, March 2024, version 05, p. 28. 

7. Obligations of the sponsor after the clinical trial has been authorised

After the trial has been authorised, the sponsor has several obligations, such as the reporting of suspected unexpected serious adverse reactions (SUSARS) in accordance with Regulation (EU) No 536/2014 – Chapter VI – Article 42.

See below the information the sponsor must notify, as provided by the Clinical Trials Coordination and Advisory Group, Clinical Trials Regulation (EU) No 536/2014 in practice, March 2024, version 05, pp. 29-30.

8. After the end of the clinical trial

Once the clinical trial has ended, the sponsor shall notify the end or early termination of the CT, submit to CTIS a summary of the results, and submit to CTIS a clinical study report where the clinical trial was intended to be used for obtaining a marketing authorisation for the investigational medicinal product.

There are also archiving obligations for both the sponsor and the investigator: The sponsor and investigator must retain the contents of the clinical trial master file for a minimum of 25 years following the trial’s completion. Participants’ medical records must be preserved in compliance with applicable national regulations.
 

9. Transparency

Regulation (EU) No 536/2014 also provides for high standards for transparency and publication of clinical trials data in the European Union to ensure trust and access to valuable information for researchers, health care professionals, patients and the general public.

For more information on the practical steps of clinical trials authorisation in the EU in accordance with Regulation (EU) No 536/2014, please see:

• the Clinical Trials Coordination and Advisory Group, Clinical Trials Regulation (EU) No 536/2014 in practice, March 2024, version 05
• the Clinical Trials Coordination and Advisory Group, clinical trials Regulation (EU) No 536/2014 Questions & Answers version 7.2, 27 March 2026
• The European Commission webpage on Clinical Trials

Published: 13/05/2026

Authors:

Luc-Sylvain Gilbert, EuroGCT information officer on Ethical, Legal and Societal Issues

Edouard Habib, EuroGCT ELSI Legal Information Officer

Aurélie Mahalatchimy, EuroGCT WP4 Convenor, UMR 7318 DICE CERIC, Aix-Marseille University, CNRS, Aix-en-Provence, France