Author: Dr. Judit Balogh
The European Parliament and the Council of the European Union adopted the Regulation 536/2014 on clinical trials on medicinal products for human use („Clinical Trial Regulation”/CTR, hereinafter referred to as „Regulation”), and repealed Directive 2001/20/EC on 16th April 2014.
Although, this Regulation has been in force since 2014, the new system’s introduction was linked to the full operation of the EU portal and database, which was originally expected in 2018, but it was delayed several times.
In spring 2021, the suitability of such systems was determined by a required independent audit, which was promulgated by the Council’s Regulation in the Official Journal of the European Union on 31st July, 2021. In this way, the condition for the application of the Regulation was fulfilled and – according to the law – following 6 months from the publication – i.e. following the date of 31 January, 2022 – the Regulation shall be applicable.
As we see in the introduction, the Regulation is a result of a long process of harmonization, the first step of which was the creation of the 2001/20/EC Directive on the approximation of the laws, regulations and administrative provisions of the Member State relating to the implementation of the right clinical practice in the conduct of clinical trials on medicinal products for human use (hereinafter „Directive”).
Although, the Directive has been a significant step forward in the Member State’s fragmented regulations, based on the experiences, it didn’t reached the level at which the adequate efficiency of the authorization and the database of the clinical trials in the European Union would have been resulted. Nevertheless, the Directive provided valuable experiences, which showed what areas of the regulation needed to be reorganised and developed
The aim of the Regulation was to unite and thereby speed up the authorization, conduction of clinical trials and related data providing in European Union.
According to the expectations of the European Medicines Agency the new system will create a regulatory and technical environment, which makes the European Union appreciated by its simplicity and transparency for the clinical trials and researches, together with innovations and investments, moreover, it supports the effective cooperation between the authorities and researchers
One of the cornerstone of the practical applicability of the Regulation is the so-called Clinical Trial Information System, a key element of which is the EU portal and database.
The EU portal makes the requests submission simpler and, from the start of its operation, it will be the only site for initiating the procedure for the authorisation of clinical trial in the European Union. Furthermore, the portal allows to initiate the proceeding with one request in several or all of the Member States, in other words, there is no need to submit separate requests in each Member State for the authorisation of the same clinical trial.
The CTIS will contain all relevant information in connection with the clinical trials submitted via EU portal in order to guarantee an adequate level of transparency, promote the cooperation between the Member States and as well as ensure the appropriate information to the EU citizens.
Another advantage of CTIS is that the system will be publicly available and the data will be contained in an easily searchable format, so the documents of the same clinical trial will be easily accessible, moreover, other clinical trials will be accessible where the same investigational medicinal was used. In order to achieve these aims, the database identifies each clinical trial with a unique identification number and following thereof, every relevant party shall refer to this number during the further proceedings.
There are only a limited number of exceptions to the presentation and disclosure of data. For example, the personal data of the subjects as well as and data for which there are special reasons not to disclose the, e.g. the protection of the right of individual and personal data.
The most significant innovation of the new regulation is that these requests for permission of clinical trials must be submitted through the EU portal in the future. In the request the Member State concerned needs to be marked, thereby it won’t be necessary to submit separate requests in each member states.
Following the submission of the application, as default setup, the evaluation will be divided two parts. In the first part, the reporting Member State appointed under the Regulation evaluates the request considering the aspects of the Regulation[1], then prepares an assessment report on the basis thereof. This will be the first part of the assessment report, which contains one of the following conclusions:
a) the conduct of the clinical trial is acceptable
b) the conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions
c) the conduct of the clinical trial is not acceptable
Contrary to the general rule for clinical trials involving more than one Member State, the procedure has three parts: (i) an initial assessment phase, (ii) a coordinated review phase involving all member states and (iii) a consolidation phase performed by the reporting Member State.
In the second part of the assessment the Member States concerned in their own territory shall check the application by the Regulation’s aspects[2], then they shall prepare the second part of the assessment report.
At the end of the assessment, a decision is made whether the clinical trial may be authorised, may be authorised with certain conditions or the authorisation may be not authorised.
It is essential that the conclusion of reporting Member State in the first part of the assessment is deemed to be the conclusion of all of the Member States. By contrast, if the reporting Member State declares the clinical trial acceptable (or acceptable with specific conditions), the Member States concerned shall be entitled to refuse authorization only in exceptional cases specified in the Regulation.
The decision is also published through the EU portal.
Further additional key element of the Regulation is that it requires a data providing obligation in connection with the clinical trials. In the frame thereof, the sponsor shall submit a summary on the clinical trial to EU database within one year following the closure of the clinical trials in all Member States independently from the result thereof. A summary shall be also attached with non-professional wording. The content of the summary is also regulated by the Annex of Regulation.
Furthermore, where the clinical trial was intended to be used for obtaining a marketing authorisation for the investigational medicinal product, the applicant for marketing authorisation shall submit to the EU database the clinical study report after the day the marketing authorisation has been granted.
As we mentioned above, the Regulation and the CTIS are applicable from 31st January 2022, however, requests submitted before the above date will be subject to the previous regulation for 3 years thereafter. If the request is submitted between 6 and 18 months after 31st July 2021, the clinical trial may be started according to the Articles 6, 7 and 9 of the Directive and the Directive’s regulations shall be applicable for 42 months from 31st July, 2021.
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[1] For example therapeutic and public health benefits, the risks and inconveniences for the subject, compliance with the labelling requirements set out in the Regulation, compliance with the requirements concerning the manufacturing and import of investigational medicinal products and auxiliary medicinal products set out in the Regulation
[2] For example compliance with the requirements for informed consent, compliance of the arrangements for rewarding or compensating subjects with the requirements, compliance of the arrangements for recruitment of subjects with the requirements, etc.
