Authors: Václav Audes, Kateřina Slavíková
On 31 January 2022, the “new” 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 (the “Regulation“) will enter into force. After several delays (the launch was originally planned for 2015), the European Medicines Agency (the “EMA”) has confirmed to the Commission that the EU portal and the EU database, which were a prerequisite for the launch, are now fully functioning. At the same time, the EMA confirmed that the EU portal and database will be put into operation on 31 January 2022. As of this date, the Regulation will become fully applicable in all EU Member States.
The EU portal will serve as a single “entry” (communication) point for the submission of data relating to clinical trials. Henceforth, applications for clinical trials will be submitted through this portal only (and not to all local administrative bodies) and will be assessed through this portal. All data will be stored in a publicly accessible EU database (that is to avoid unnecessary duplication with the EudraCT and Eudravigilance databases, as expressly stated in the Regulation).
Besides applications for the authorisation of a clinical trial, sponsors will also submit through the EU portal, for example, notifications of the start, temporary halt or termination of a clinical trial in each Member State, as well as a summary of the results and a clinical study report.
Although it will be a public database, some data will be excluded from publication. For example, the personal data of data subjects or confidential information of a commercial nature, in particular with regard to the status of marketing authorisation of a medicinal product, “unless there is an overriding public interest in disclosure”.
It will be interesting to see how the concept of public interest evolves, as, particularly in the current pandemic era, COVID 19 medicinal products and vaccines are very often discussed in the media even before they are authorised. Other exemptions from disclosure will include, for example, confidential communications between Member States in connection with the preparation of an assessment report and data needed for effective supervision over clinical trials across the EU.
The Regulation aims to ensure uniform rules for conducting clinical trials across the EU. To this end, it introduces in particular an authorisation procedure based on a single submission via the EU portal and an evaluation procedure leading to a single decision. The submitted application will be assessed by all Member States concerned for their own territory in the light of specified aspects, providing that the decisive conclusion on the acceptability of the clinical trial will be made by the reporting Member State. The Member States concerned may disagree with this conclusion only on the grounds listed in the Regulation.
The Regulation is also intended to harmonise rules for the protection of subjects, including requirements for informed consent. In this context, the Member States are free to decide regarding the signatures of an incapacitated person and a minor who is capable of forming an opinion and assessing the information obtained.
The Czech legislature took advantage of the possibility for minors and, by an amendment to Act No. 378/2007 Sb., on Pharmaceuticals and on Amendments to Certain Related Acts (the “Act on Pharmaceuticals”), it included a requirement for the consent of a minor where it is appropriate to his or her intellectual and volitional maturity. In the Czech Republic, persons with limited legal capacity as well as other groups of persons in a “subordinate or dependent position” may only be subjects of trials under stricter and exceptional conditions (set out beyond the scope of the Regulation).
The harmonisation will also affect safety reporting. The Eudravigilance database operated by the EMA is now expected to allow for joint reporting when more than one investigational medicinal product is involved in a clinical trial. Only in the case of serious unexpected adverse reactions will the Czech Act on Pharmaceuticals allow the Czech State Institute for Drug Control (the “SIDC”) and the sponsor to enter into an agreement, subject to the requirements set out in the Regulation, under which the sponsor will report suspected serious unexpected adverse reactions directly to the SIDC (that will further report them to the EMA). It is open to consideration whether or not the conclusion of the agreement (leading to dual reporting) will be a practical benefit for sponsors that they will use after the Regulation comes into force.
Jointly with the Regulation, the Commission Regulation on good manufacturing practice for investigational medicinal products for human use[1], including detailed Commission guidance on the same[2], will also enter into force.
As for archiving periods, a clinical trial master file should, under the Regulation, be retained for 25 years after the end of the clinical trial, on media ensuring the completeness and legibility of the content throughout that period, so that it can be made available to the competent authorities upon request. This is expected to harmonise the fragmented implementation of the periods in the Member States.
For the Czech Republic, it should also remove the uncertain situation where, in 2017, in anticipation of the Regulation coming into force, the Czech legislature deleted certain provisions from the Act on Pharmaceuticals to avoid conflicts with the Regulation (which, however, is only now coming into force).
As a result, for the Czech Republic, the current Czech regulations used only the minimum 15-year period for the retention of identification codes, and the sponsors have already now resolved the often difficult issue of archiving periods for those 25 years applicable to all Member States in which the clinical trial took place. It should be added that the retention periods for pharmacovigilance and medical records are not subject to this harmonisation.
The Regulation will only apply within the EU. However, its principles regarding the rights and protection of subjects and the robustness of the data generated in the trial should also be complied with for those clinical trials conducted outside of the EU and are to be the basis on which an EU marketing authorisation application is to be filed.
Current clinical trials will be subject to a transitional regime. The Regulation provides that if an application for authorisation of a clinical trial was submitted before the effective date of the Regulation under Directive 2001/20/EC (the “Directive”), such clinical trial will continue to be governed by the Directive until three years after the effective date of the Regulation, i.e. until 31 January 2025.
If the application is submitted between the sixth and eighteenth month after the publication of the notice on the functionality of the EU portal in the Official Journal of the European Union, the clinical trial (of the sponsor’s voluntary choice) may be started in accordance with the Directive and will be governed by the Directive for 42 months from the date of the notice. Thereafter, clinical trials are to be fully subject to the regime of the Regulation.
[1] Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017 supplementing Regulation (EU) No. 536/2014 of the European Parliament and of the Council by specifying principles of and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections.
[2] Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No. 536/2014.
