Initial experiences with the Clinical Trials Regulation and CTIS in Germany

The EU Clinical Trials Regulation (EU) 536/2014 (the CTR) became applicable on 31 January 2022. We asked our best friend firm in Germany, Graf von Westphalen, to give us an insight into how the CTR and the related Clinical Trials Information System (CTIS) are bedding in.

Birgit Lotz and Sebastian Clermont write:

Clinical trials have long been an integral part of the procedure to receive a marketing authorisation for a medicinal product in Germany. Therefore, pharmaceutical companies were dealing with this issue long before the date of applicability of the CTR on 31 January 2022.

Although the general intention of the CTR is to harmonize clinical trial procedures within the EU, member states were given the option of providing supplementary regulations. Germany has made use of this option, and we note the following interesting points.

1. Sections 40 - 42c German Medicinal Products Act (the AMG)

After the CTR came into force in 2014, the German rules on clinical trials were substantially revised and supplemented in 2016, leading to changes including new Sections 40-42c AMG. Official statistics compiled by the Paul-Ehrlich-Institut (PEI) and the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) show that these changes had no relevant impact on the number of applications for authorisation.

2. Responsibility

If a pharmaceutical company intends to initiate a clinical trial in Germany, the type of the medicinal product will determine which authority is responsible for the authorisation procedure. The BfArM is generally in charge whereas the PEI has special responsibility for the authorisation of sera, vaccines, blood preparations, tissue preparations, allergens, advanced therapy medicinal products, xenogeneic medicinal products, and genetically engineered blood components.

3. Required insurance

Section 40a AMG requires the applicant pharmaceutical company to provide evidence of an insurance policy to protect trial participants, covering the possibility of death or injury to a participant’s physical integrity or health during the performance of a clinical trial.

The insurance must cover an amount of at least 500,000 EUR to be provided in the event of the death or permanent disability of a participant. The calculation of the total amount of coverage must always be based on an individual risk calculation. Payment of pain compensation is not mandatory.

4. Children as clinical trial participants

An applicant who intends to include participants under the age of 18 in a clinical trial must observe the special regulations of Section 40b (3) AMG. This contains a diversion from the CTR concerning the consent of minors.

While the CTR defines the term "minor" as a person who has not reached the mental maturity to consent to the performance of the clinical trial after being appropriately informed, German law in general distinguishes between minors and adults based on the completion of the 18th year of age.

Due to this divergent understanding the German legislator used the opening clause in Article 29 (8) of the CTR: "For subjects under the age of 18, the consent of both parents is mandatory. If the minor is able to give an informed consent, this is additionally necessary in addition."  

5. Clinical Trials Information System (CTIS)

One major achievement of the CTR is the introduction of a digital solution for clinical trial applications. On 31 January 2022, the CTIS homepage was released, and since that date, all initial applications for authorisation of a clinical trial must be submitted via CTIS. The transfer of all pending clinical trials to CTIS must be completed by 31 January 2025.

The structure of CTIS homepage is the same for users in Germany as elsewhere in the EU.

Importantly, while an application for authorisation of a clinical trial can be submitted in either English or German, documents for participants as well as the labeling of investigational and auxiliary medicinal products must be submitted in German.

In the course of submitting applications via CTIS, initial users from Germany have raised a number of criticisms:

  • the feedback in English, in that the questions were not phrased clearly enough, which may cause inaccurate or insufficient answers
  • technical problems like incorrectly calculated deadlines or officially requested but technically impossible submissions of corrected country-specific documents
  • that CTIS offers no direct communication with authorities and ethics committees

Positive comments indicate that:

  • Some technical errors have been fixed in the initial period
  • German regulations allow a pharmaceutical company direct communication with the responsible ethics committees by applying for fee-based advice prior to the application, as the ethics committee and its contact details remain unchanged during the whole application procedure
  • For detailed information on CTIS, the BfArM provides a FAQ-page in English: BfArM-CTIS.

As might be expected, there are a number of initial problems with the implementation of the new system and users are pressing for these to be resolved. In addition, the German implementation shows that the system will not introduce complete uniformity across the EU. However, a greater degree of harmonisation is likely to make the system easier for international companies to use once early issues have been addressed.

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