2. General Questions

2.1 Name of Regulatory Authority

Paul-Ehrlich-Institut (“PEI”) and the Federal Institute for Drugs and Medical Devices/Bundesinstitut für Arzneimittel und Medizinprodukte (“BfArM”) are the respective competent federal higher authorities. Clinical trials are approved in Germany by the BfArM or the PEI depending on the type of product to be used in the trial.

The Federal Ministry of Health/Bundesministerium für Gesundheit (“BMG”) is the highest federal government department responsible for health in the Federal Republic of Germany.

The PEI and BfArM are under the Ministry’s technical and administrative supervision, regulating medicinal products in Germany. 

The PEI is the Federal Institute for Vaccines and Biomedicines and is responsible for approving clinical trials in the field of vaccines and biomedicines. Pursuant to Section 77 of the German Medicinal Products Act/Arzneimittelgesetz (AMG), the PEI’s responsibility concerns the following Human Medicinal Products, and the authorization of clinical trials for human use involving these products:

• Sera
• Vaccines
• Blood preparations
• Tissues and tissue preparations
• Allergens
• Advanced therapy medicinal products (gene therapeutics, somatic cell therapeutics, and biotechnologically manipulated tissue products)
• Xenogenic medicinal products
• Genetically engineered blood components

The BfArM is the competent authority in Germany for medicinal products not listed under the PEI’s specific responsibility. It also authorizes proprietary medicinal products.

The GCP Inspections Unit of the BfArM is responsible for ensuring compliance with the regulatory requirements of the BfArM and European Medicines Agency (“EMA”) in relation to clinical trials involving medicinal products for which the PEI does not have specific responsibility.

2.2 Name of Ethics Committee

In accordance with Section 41a of the AMG, only public-law ethics committees of the federal states may participate in the procedure for the evaluation of clinical trials with medicinal products for human use in accordance with CTR 536/2014.

As per what is established in Section 41a- Paragraph 6 of the AMG, the BfArM publishes the list of registered ethics committees in the Federal Gazette.

The latest announcement took place on 07 Feb 2023. As of this date, there are 33 Ethics Committees for medical research in Germany that can take part in the review of clinical trials as per the CTR 536/2014.

The Association of Medical Ethics Committees (AKEK) is the association of public ethics committees that review biomedical research projects in Germany.

2.3 Clinical Trial Application Language

The application for authorization of a clinical trial to be submitted in accordance with Article 5(1) of the CTR 536/2014 shall be submitted via the Clinical Trial Information System (CTIS) in German or English.

Documents that are intended for the study participant and his/her legal representative must be submitted in German.

All labels (for investigational medicinal products) as well as any auxiliary products must be submitted in German.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes. Approval of a clinical trial by the BfArM or PEI is required in addition to a favorable opinion from the competent Ethics Committee. 

2.5 Can regulatory authority and EC submission be done in parallel?

Yes. A single application submission for Part I (intended for PEI or BfArM review) and Part II (intended for EC review) can be submitted in parallel through the EMA CTIS portal.

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

Yes.

The Central Customs Authority in Germany (“ZOLL”) monitors the import and export of medicinal products and active substances within the scope of the German Medicinal Products Act. Their website describes the aspects of this monitoring as ensuring that:

• the required import permits, certificates, and certifications have been obtained;
• the medicinal products have been approved, registered, or licensed;
• the labeling requirements have been complied with; and
• finished medicinal products from the pharmaceutical industry include a package leaflet in German.

The Central Customs Authority will inform the competent RA of any suspicion of an infringement, and presentation of the consignment to that authority ordered, at the expense and risk of the party at whose disposal the goods are.

"Import" within the meaning of the Medicinal Products Act is the release for free circulation of goods falling within the scope of the Medicinal Products Act, coming from all non-EU states, with the exception of those from Iceland, Liechtenstein, and Norway.

Medicinal products and certain active substances to be imported to Germany

When importing medicinal products or certain active substances, an import permit is required, in accordance with Section 72 of the Medicinal Products Act, and a certificate from the country of origin is required, in accordance with Section 72a of the Medicinal Products Act, which confirms compliance with the quality standards, and/or an appropriate certification from the medicinal products authority competent for commercial imports in the municipality where an importer’s business is established.

Imports of medicinal products or active substances from Iceland, Liechtenstein, and Norway (EEA member states) can be released for free circulation in Germany without the presentation of medicinal product legislation documents (not seen as an import within the meaning of the Medicinal Products Act).

Tissue and certain tissue preparations to be imported to Germany

For the import of tissues and/or certain tissue preparations, an import permit is required, pursuant to Section 72b (1) of the Medicinal Products Act, from the competent regional authority, as well as a certificate from the state of origin pursuant to Section 72b (2) of the Medicinal Products Act, which confirms that the standards observed during the extraction and processing of the tissue/tissue preparations are at least equivalent to the standards of good practice laid down by the European Union (Good Manufacturing Practice - GMP).

Pursuant to Section 21a (9) of the AMG, a certificate from the Paul-Ehrlich-Institut is required for the first introduction of tissue preparations from Iceland, Liechtenstein, or Norway, to Germany.

Certificate for customs clearance pursuant to Section 73 (6) of the AMG.

For the import of finished medicinal products, a certificate from the medicinal products authority competent for the consignee is required for customs clearance; the certificate must state the type and quantity of the medicinal products and confirm that the prerequisites for marketability within the scope of the Medicinal Products Act have been met and that the importer has obtained the required import permit.

According to Section 22(5) of the German Medicinal Products Act, if a medicinal product (finished medicinal product or bulk product) is manufactured in countries that are not member states of the European Union or contracting states of the Agreement on the European Economic Area, evidence must be provided in the approval procedure that the manufacturer complies with the regulations of the country of manufacture is entitled to manufacture medicinal products. In addition, the importer must present an import permit (import permit) in accordance with Section 72 of the German Medicinal Products Act, as described above.

The import permit must be applied for in the EU/EEA country to which the medicinal products are to be shipped.

A translation into German or English prepared by a publicly appointed or sworn interpreter or translator must be attached to the import permit.

If there are delays in obtaining the import permit, written confirmation from the competent authority must be submitted in advance, documenting that an import permit has been applied for.

However, an import permit according to Section 72 of the German Medicinal Products Act (cf. Section 22 (5)) must be submitted before the procedure is completed since the lack of an import permit can lead to the rejection of the application for approval according to Section 25 (2) No. 1 of the German Medicinal Products Act.

Additionally, more information on import permits for finished products can be found on the BfArM website -  Information on submitting applications for authorization in de decentralized procedure (according to the Art 28 (3) of Directive 2001/83/EC).

Information regarding the manufacturing authorization and import authorization is available in a Q&A format on the BfArM website - Manufacturing authorization/ import authorization.

2.7 Biological Specimen Export Requirements

Yes. The Federal Government’s export control policy is administered by the Federal Office for Economic Affairs and Export Control. Dual-use items, which are those that may be used for civil and military purposes, are subject to controls. The Federal Office for Economic Affairs and Export Control decides on the granting or refusing of authorization after taking into consideration all the available information about the intended use.

It is noted that the science and research sectors are subject to the same export controls as other sectors. The Federal Office for Economic Affairs and Export Control has published guidance entitled “Export Control in Science & Research” which states that “control regulations equally apply to private individuals such as scientists, but also to legal entities such as research institutions or developing and manufacturing companies - regardless of the motivation and purpose of their activity. The objective potential for misuse is the sole criterion”.

Forms, and contact details in order to establish whether a license may be granted, are available at the Federal Office for Economic Affairs and Export Control webpage.

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes, if the specified criteria are met.

Details of the requirements and procedure to follow are available at the Paul-Ehrlich-Institut website, Clinical trial authorization with genetically modified organism (GMO).

2.9 Is in-country sponsor presence/representation required?

Not specifically in Germany, but the Sponsor must be present or represented in an EU or EEA member state.

Section 40a(1) of the German Medicinal Products Act states that “there is a sponsor or a representative of the sponsor must have a registered place of business situated in a Member State of the European Union or in another State Party to the Agreement on the European Economic Area”.

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country?

The German Medicinal Products Act is silent in this respect. 

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator?

No, under the EU Clinical Trial Regulation 536/2014, there is no role for Chief or Coordinating Investigator, only Principal Investigator and Investigator.

Section 4(25) of the German Medicinal Products Act defines an investigator as the person within the meaning of Article 2 (2) (15) of the Regulation (EU) 536/2014, and a Principal investigator as the person within the meaning of Article (2) (16) of the Regulation (EU) 536/2014.

The definitions within the EU Clinical Trials Regulation 536/2014 referred to above, are as follows:

Art. 2 (2) (15): “Investigator” means an individual responsible for the conduct of a clinical trial at a clinical trial site.

Art. 2 (2) (16): “Principal Investigator” means an investigator who is the responsible leader of a team of investigators who conduct a clinical trial at a clinical trial site.

Investigators participating in clinical trials must be trained according to the Curriculum of the Bundesärztekammer and the Working Party of German Ethics Committees Arbeitskreises Medizinischer Ethik-Kommissionen.

The Association of Medical Ethics Committees, together with the Executive Board of the German Medical Association and the Standing Conference of the Management and Chairs of the Ethics Committees of the State Chambers of Physicians, prepares the curricula for the continuing education of physicians who wish to participate in a clinical trial.

The investigator must hold a medical license.

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled?

A written contract is required between the sponsor and the CRO, delegating authority. The contract does not need to be notarized and/or apostilled, so far as we are aware, at an EMA level, now that applications are made electronically.

Article 71, EU CTR 536/2014, provides clarification on the sponsor's role:

“Sponsor

A clinical trial may have one or several sponsors.

Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution, or an organization. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial.  The investigator and the sponsor may be the same person.”

2.13 Is there a requirement to register clinical trials on a local registry or database?

Yes. From the 31^st of Jan 2023, all initial clinical trial applications in the EU/EEA must be submitted through the Clinical Trials Information System (CTIS). The status and results of all trials submitted under the CTIS will be available to the public.

EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trials Regulations 536/2014 are publicly accessible through CTIS. 

Additionally, the German Clinical Trials Register (DRKS) is the German WHO primary registry. It is responsible for the registration of all health-related studies on humans conducted in Germany. 

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

The requirement is 25 years from the end of the clinical trial. The specific format is not prescribed, but it must be traceable, legible, and accessible upon request. 

See Article 58, EU CTR 516/2014

“Archiving of the clinical trial master file

Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law.

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

The sponsor shall appoint individuals within its organization to be responsible for archives. Access to archives shall be restricted to those individuals.

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

Any alteration to the content of the clinical trial master file shall be traceable.”

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

Relevant provisions on periodic safety reporting are a part of the EU CTR 536/2014.

Articles 41 & 42, EU CTR 536/2014, relate to this.  

Art 41 CTR: “Reporting of adverse events and serious adverse events by the investigator to the sponsor

1. The investigator shall record and document adverse events or laboratory abnormalities identified in the protocol as critical to the safety evaluation and report them to the sponsor in accordance with the reporting requirements and within the periods specified in the protocol.

2. The investigator shall record and document all adverse events, unless the protocol provides differently. The investigator shall report to the sponsor all serious adverse events occurring to subjects treated by him or her in the clinical trial, unless the protocol provides differently.

The investigator shall report serious adverse events to the sponsor without undue delay but not later than within 24 hours of obtaining knowledge of the events, unless, for certain serious adverse events, the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an impact on the benefit-risk balance of the clinical trial...”

Art 42 CTR: “Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency

1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without delay to the database referred to in Article 40(1) all relevant information about the following suspected unexpected serious adverse reactions:

(a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred at a clinical trial site in the Union or in a third country;

(b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:

(i) by that sponsor, or

(ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product or information to a future potential marketing authorization holder on safety matters shall not be considered a joint development; and

(c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.

2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency shall take account of the seriousness of the reaction and shall be as follows:

(a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction;

(b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than 15 days after the sponsor became aware of the reaction;

(c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or non-life threatening but which turns out to be fatal or life-threatening, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening….”.

Guidance on the reporting of SUSARs is available on the BfArM website.

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

Annual reports of clinical trials falling within the scope of the EU CTR 536/2014 shall be submitted to the EMA Clinical Trials Information System (CTIS).

Article 43, EU CTR 536/2014:

“1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor.

2. In the case of a clinical trial involving the use of more than one investigational medicinal product, the sponsor may, if provided for in the protocol, submit a single safety report on all investigational medicinal products used in that clinical trial.

3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymized data.

4. The obligation referred to in paragraph 1 starts with the first authorization of a clinical trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor with the investigational medicinal product…”.

There are also other reporting/notification requirements, that will be required to be performed within the CTIS, those are:

2.17 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol?

Yes, notification is required within seven days of becoming aware of the breach (see details below).    

Notification of a Serious Breach allows the sponsor to inform about a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial. These notifications must be made without undue delay but no later than 7 days from the date on which the sponsor became aware of the breach (article 52 of the CT Regulation). 

For more information, refer to the following EMA guidance on notification of serious breaches: 

1. Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol 
2. Appendix III b – Information to be submitted with a notification of a serious breach

2.18 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

Yes, insurance is required in the amount of at least €500,000 per participant.

Section 40a (3) of the German Medicinal Products Act requires insurance to be “taken out in favor of the person concerned in a clinical trial with an insurance carrier authorized to conduct business in a Member State of the European Union or another State Party to the Agreement on the European Economic Area. Its scope must be reasonably commensurate with the risks involved in the clinical trial and determined on the basis of the risk assessment in such a way as to ensure that for every case of the death or permanent occupational disability of a person concerned by clinical trial, at least 500,000 euros are available”.