The Clinical Trials Regulation no. 536/2014 was applied from 31 January 2022. The new regulation applies to all clinical trials of medicinal products for human use in the European Union. The new regulation does not apply to non-interventional studies.
The aim of the new regulation is to make the European Union more attractive destination for pharmaceutical research and development. The regulation harmonises different processes concerning the application for authorization, evaluation and supervision of clinical trials in the European Union and the European Economic Area.
- The EU Clinical Trials Information System (CTIS) will be used to submit clinical trial applications.
- One trial application = one set of documents.
- The Member States involved will jointly assess the application. Each Member State will decide whether to authorize the study or not.
- The application consists of two parts: Part I (common for all countries) and Part II (country-specific).
- There are clear deadlines for evaluating the application, which are also followed by the ethics committees.
- Simplified notification procedures that do not require sponsors to provide similar information to different authorities in different Member States .
- Clinical trials conducted outside the EU referred to in the application must comply with EU requirements.
- Increased transparency of clinical trials data.
- The Commission will have the right to inspect clinical trials in Member States and in third countries.
The clinical trial application consists of two parts: Part I (common for all Member States) and Part II (country-specific). Joint assessment applies to both clinical initial applications and applications for substantial modifications (SM). In a joint assessment, the Reporting Member State will prepare an Part I assessment report, which the other Member States Concerned can comment on, and add their own considerations.
The requirements for the application dossier are set out in Annex I of the Regulation no 536/2014.
The general requirements and templates for Part II documents are available in the European Commission's guide Eudralex vol 10.
Application for substantial modification
EU Clinical Trials Information System (CTIS)
The regulation allows the sponsor to submit one single application through the Clinical Trials Information System (CTIS) to all countries where the study is to be conducted, and the national competent authorities and the ethics committees will evaluate the application in cooperation. It will also be easier to extend existing clinical trials to other countries in the European Economic Area.
For more information, please contact the European Medicines Agency directly via [email protected].
The European Medicines Agency (EMA) has developed an online training program on CTIS.
In addition to the training program, a sponsor handbook has been published.
More information on the training and materials provided by CTIS and EMA can be found here.
In addition, the portal allows Member States to jointly assess safety data from ongoing studies. This provides a better overview of the risk-benefit balance of investigational medicinal products.
All clinical trial documents to be reported by the sponsor, including notifications, substantial modifications, annual safety reports (ASRs), the final study report and the results, are submitted through the portal.
The exception is SUSAR notifications, which must be submitted directly by the sponsor to the EudraVigilance database.
The new regulation provides for a transitional period of three years. Within one year, until 31 January 2023, sponsors may submit applications under either the new Clinical Trials Regulation or the current legislation (based on the Clinical Trials Directive). From 31.01.2023, the submission of applications under the new regulation will become mandatory. By 31 January 2025, all ongoing studies must comply with the requirements of the regulation and the study data must be transferred to the CTIS.
Applications under Directive 2001/20/EC
Until 31.01.2025 it is possible to submit applications for Substantial Amendments to trials authorised under the Directive, as before. SA applications under Directive 2001/20/EC must comply with the Directive and the corresponding national legislation.
For applications for Substantial Amendments, it is necessary to send the completed Annex II form and to attach the track changes version(s) of the documents.
The cover letter should indicate whether the application is submitted to both the ethics committee and the SAM, and to whom the SAM will send the invoice for the specialised assessment fee. Applications for Substantial Amendments submitted to the Agency should be sent to [email protected]
Decisions on Substantial Amendments submitted to the ethics committee will be issued as an administrative decision of the Agency: the .asice container signed by the Agency will contain the approval of the ethics committee.
Medicinal Products Act and regulations of the Minister of Social Affairs:
- Rules of procedure of medical ethics committee for clinical trials, a list of data to be submitted for obtaining approval, procedure for adoption of resolutions and format of application for obtaining approval
- Procedure for reporting serious adverse events occurring in clinical trials
- Conditions and Procedure for Conducting Clinical Trials of Medicinal Products
Evaluation fees of an application for a clinical trial of a medicinal product are outlined in the regulation of the Minister of Social Affairs.
Safety reporting in clinical trials that comply with the Directive is carried out as before: SUSARs are reported directly to the EudraVigilance database (it is not necessary to send them to the State Agency of Medicines), DSURs should be sent to [email protected]
The list of Part I documents can be found in EU Regulation no 536/2014 Annex I, points B to J.
Estonia has no specific requirements for cover letters.
See European Commission Eudralex vol 10 for various guidelines.
Country-specific requirements can be found in the European Commission Eudralex vol 10 Questions and Answers Document Annex II.
We encourage the sponsors to share their plans with SAM if Estonia is to be proposed as a Reference Member State (RMS) in a clinical trial application. We can be reached by e-mail at [email protected].
The Clinical Trials Ethics Committee accepts templates issued by the European Commission (Part II application document templates).
List of Part II documents can be found in EU Regulation No 536/2014 Annex I, points K to R.
K. Recruitment arrangements - Informed consent and patient recruitment procedure template + recruitment materials to be used;
L. Subject information, informed consent form and informed consent procedure - Informed consent and patient recruitment procedure template. All materials to be provided to subjects must be provided in all languages in which they are intended to be used.
An ICF template is available on the Agency's website that has been approved by the ethics committee.
M. Suitability of the Investigator - Investigator Curriculum Vitae template. It is compulsory to submit a CV in English, dated and signed by the Principal Investigator of the trial site. The CV must include information on the most recent GCP training.
N. Suitability of the facilities - Site suitability form. The form must be signed by a person legally authorised by the study centre. Estonia accepts digital signatures and manually signed paper. CTIS does not allow upload of .asice files, therefore it is accepted in CTIS to upload a .pdf file; however, the original .asice file must be available at the study centre.
Two versions should be uploaded to CTIS: 'for publication' and 'not for publication'. In the version to be made public, sensitive personal data (e.g., signatures) must be masked or removed.
O. Proof of insurance cover or indemnification.
P. Financial and other arrangements - Compensation for trial participants template. Transparent information on the budget of the trial must be provided. The fee per patient can be taken as a basis and a description of how it is broken down. It should also be confirmed that no trial-specific services will be billed to the Estonian Health Insurance Fund. The submission of a declaration of interest is not mandatory.
Q. Proof of payment of fees - not applicable; SAM will issue an invoice for the specialised assessment fee within 10 days after the clinical trial application has been accepted. Please include the invoice recipient's details in the uploaded file.
R. Proof that data will be processed in compliance with Union law on data protection - Statement on compliance Regulation (EU) 2016/679 template. In addition, the study sponsor must ensure that all data protection aspects are explained in detail in the patient information leaflet. It is recommended that the patient can give two consents in the information sheet: one for participation in the study and one for the use of their health data/biological samples in pseudonymised form.
In addition: a description of the handling of biological samples. Please describe what will be collected, how it will be collected (pseudonymised or anonymised), how it will be transported, where it will be stored, how long it will be stored (years) and when it will be destroyed.
Further requirements on data protection can be found here:
For country-specific language requirements, please refer to Annex II of the European Commission's Eudralex vol 10 Questions and Answers Document.
Applications for Substantial Amendments (complying with the Directive), enquiries concerning the requirements of Part II documents of Regulation (EU) No 536/2014 and questions for the ethics committee should be sent electronically to [email protected].
An appeal against a decision on the authorisation of a clinical trial may be submitted to the Medicines Agency within 30 days of notification of the decision in accordance with § 71(1) of the Administrative Procedure Act. If the recipient of the decision wishes to challenge the decision before an administrative court, he or she may lodge an appeal against the decision with the Tartu Administrative Court within 30 days of notification of the decision, in accordance with § 7(1) and § 46(1) of the Code of Administrative Court Procedure.
In order to comply with the new regulation, changes will also be made in Estonian legislation.
Evaluation fees of an application for a clinical trial of a medicinal product
Clinical Trials Regulation no 536/2014
Clinical Trials Regulation no 536/2014 Q&A document
Eudralex vol 10; Chapter I – Application and application documents
Clinical trials contact in the Estonian State Agency of Medicines: [email protected]
Last updated: 29.01.2023