On January 31, 2022, the Regulation of the European Parliament and the Council of the European Union on clinical trials of medicinal products for human use came into force, repealing Directive 2001/20/EC at the same time.
What the CTR actually is?
The Clinical Trials Regulation is a regulation containing provisions on clinical trials. To better understand the whole problem, it is necessary to consider what they are and what aspects clinical trials contain.
“Clinical trial” means a clinical study – any investigation in relation to humans intended to discover or verify effects of one or more medicinal products, to determine safety and effectiveness of those medicinal products. The former concept of clinical trial needed to be clarified by introducing a broader concept of biomedical research. The issue of the terms introduced in the Regulation will be discussed in more detail at the end of the article.
Clinical Trials Regulation entered into application ensures that the EU offers an attractive and favorable environment for large-scale clinical trials with high standards of public transparency and safety for clinical trial participants. Briefly, the CTR aims to ensure that medicines are effective and safe to use by making the whole process more efficient and trials more transparent. That will allow public searches and patients to learn about this trials in the EU.
CTIS – what is the new platform supposed to be used for?
Access to information was facilitated by the establishment of the system called Clinical Trials Information System (CTIS). The CTIS supports the flow of information between clinical trial sponsors, EU, Member States European Economic Area countries and the European Commission.
The CTIS is a single entry point for sponsors and clinical trial regulators for the submission and evaluation of clinical trial data, which includes a publicly accessible, searchable database for healthcare professionals, patients and the general public.
Thanks to the system, sponsors will no longer have to submit clinical trial applications separately to the National Competent Authorities (NCAs) and Ethics Committees in each country to obtain regulatory approval to conduct a clinical trial, and the registration and publication of results will no longer be completely separate processes.
Therefore, it can be expected that the simplification of this procedure will significantly reduce the time needed to start the study.
What is the purpose of this regulation?
The legislation has taken the legal form of a Regulation and replaced national law, in order to harmonize regulations and ensure that the conduct of clinical trials is identical across the EU. Experience shows that the legal form of the regulation would be beneficial for sponsors and researchers, for example in the context of clinical trials conducted in more than one member state. Where do these conclusions come from?
The directive decreased the effectiveness of clinical trials in the EU – in recent years, European Union countries have experienced a decline in the effectiveness of clinical trials and loss of competitiveness compared to other global markets. The directive led to discrepancies, slowed down research, and the costs of running projects increased, which significantly reduced the amount of newly registered research in the Member States.
The main idea is to create an environment that will be favourable for conducting clinical trials with the highest standards, but also will persuade to work sharing and collaborating between members.
The type of information which is required in applications for clinical trials does not change. The submission process is changing to coordinate and harmonize requests of multinational applications. The whole process is primarily about increasing efficiency and effectiveness, while emphasizing safety procedures and the importance of the individuals, which are the last link in clinical procedures.
The Regulation introduces new concepts which are a key change and are significantly different from the previous directive. The national law that dictated the conditions for implementing the new regulations was then on the pedestal. In contrast to the EU-CTD, the EU-CTR gives a higher place in the hierarchy to a regulation that dictates the conditions and binds all member states into one entirety. The method of integration is an important element of unifying communities, and the main integral component is the law of the European Union. Unlike regulations, the provisions of the directives do not apply directly, as they do not exhaustively regulate the issues that are the subject of the regulations. Therefore, they always require implementation, i.e. clarification by acts of national law. Implementation, i.e. the adaptation of the provisions contained in the directives into the national order within a specified period. It slows down the process of actual compliance with the proposed legal solutions. The form of the regulation actually imposes an obligation on the Member States to apply this law.
31 January 2022 was the day when the three-year transition period has started. There are three potentially possible solutions enabled by the new legal regulations repealing Directive 2001/20/EC which came into force eight year earlier.
From the date of entry into force of the act to 31 January 2023 sponsors may submit trials on the basis of the regulations contained in EU-CTD or EU-CTR.
From January 31 2023, all clinical trial applications are subject to the EU-CTR. Previously approved under the EU-CTD can be applied on the basis of the legal regulations in force at that time until 31 January 2025.
From January 31, 2025, all regulations are subject to the EU-CTR without any exception.
As the subtitle itself says, it is a long process that was deliberately planned in such a way that all member states could accept the new terms of the regulation and revolutionize the existing rules without compromising the clinical processes and the expected changes to failure.
What distinguishes the EU-CTR from previous EU directive?
|A single NCA1 and EC2 decision is needed for one member state, not as before both NCA and EC approvals. The Directive also introduces another new solution, where one reporting member state throughout a trial’s life cycle has to be responsible for driving the whole assessment process, moderating discussions and preparing the draft assessment report. Bearing in mind the above, sponsors need to choose their reporting member state with caution. |
NCA1 – National Competent Authority
EC2 – Ethics Committee
|Centralised electronic database|
|Mentioned earlier in the article a new portal and database called the Clinical Trial Information System (CTIS). This significantly reduces the number of steps to provide the relevant documentation. Sponsors have to enter all the necessary information using this system. Moreover, CTIS website was created to provide updates, information, resources, and results.|
|Increased public transparency|
|EU-CTR requires transparency throughout the whole development process. Disseminating awareness and understanding of clinical trials in the public is promoted in accordance with the principles of transparency, and in the final stage the results must be shared via the CTIS.|
|The regulation introduces many new concepts unknown to most people. For a better overall understanding of the act, some of them will be explained next.|
|Maximum 12 days to respond to application queries or requests for information, under pain of nullity.|
|Simplified safety reporting|
|All safety reporting via EudraVigilance, all unexpected events which affect a trial’s benefit-risk balance must be reported within 15 days.|
|Improved patient protections for vulnerable subjects|
|A natural or legal person, authority, or body which according to member state law is empowered to give informed consent on behalf of the subject who is incapacitated or a minor.|
The replacement of EU-CTD by EU-CTR is intended to result in a more efficient clinical trial submission and assessment process, unification, harmonization, computerization (by CTIS-based electronic document submission) risk reduction and much greater transparency. The legal form of the EU-CTR Regulation is more favorable to sponsors and researchers, for example in the context of clinical trials conducted in more than one Member State. Unlike regulations, directives are not of direct value effectiveness in the legal orders of the Member States. Issuing the regulation will allow to achieve all the assumptions mentioned above.
There are many positive effects already even though the regulation has entered into force relatively recently. EU-CTR:
New words appear in the regulation that are key to understanding the discussed processes. At the beginning of the article there is an explanation of the basic word in the name of the regulation. The current definition of a clinical trial as contained in Directive 2001/20/EC of the European Parliament and of the Council should be clarified. Therefore, the concept of clinical trial should be clarified by introducing a broader concept of “biomedical research” of which the clinical trial is a category. This category should be defined on the basis of specific criteria. This approach takes due account of international guidelines and is in line with Union law governing medicinal products, which is based on the division into “clinical trial” and “non-interventional study”.
“low-intervention clinical trial” means a clinical trial that fulfills all of the following conditions: the investigational medicinal products, with the exception of placebos, are authorized according to the clinical trial protocol;
“non-interventional study” means a biomedical study other than a clinical study.
The introduction of the definition of a low-intervention test will facilitate the conduct of research of great importance for the evaluation of standard treatments and diagnostics. This type of research is subject to less restrictive regulations, ultimately contributing to a high level of public health.
Questions and Answers Document – Regulation (EU) 536/2014 – Version 5 (January 2022)
Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials
Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use