5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?  

No. Local Regulations do not require a PI/CI to be approved by a Health Authority, though they must meet certain criteria as outlined in Section 2.11 of this guidebook.

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

Not specified by the national regulations.

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

Yes, if RA and EC approval has been provided. Please refer to sections 7.7 and 7.8.

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

Yes, if RA and EC approval has been provided. Please refer to sections 7.7 and 7.8.

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

See the EMA’s final Guideline of 09 March 2023 on Computerized Systems and Electronic Data in Clinical Trials which includes the following:

“6.1. Data capture and location 

The primary goal of data capture is to collect all data required by the protocol. All pertinent observations should be documented in a timely manner. The location of all source data should be specified prior to the start of the trial and updated during the conduct of the trial where applicable. 

6.1.1. Transcription 

Source data collected on paper (e.g. worksheets, paper CRFs or paper diaries or questionnaires) need to be transcribed either manually or by a validated entry tool into the EDC system or database(s). In case of manual transcription, risk-based methods should be implemented to ensure the quality of the transcribed data (e.g. double data entry and/or data monitoring).

6.1.2. Transfer 

Trial data are transferred in and between systems on a regular basis. The process for file and data transfer needs to be validated and should endure that data and file integrity are assured for all transfer. 

Data that is collected from external sources and transferred in open networks should be protected from unwarranted changes and secured/encrypted in a way which precludes disclosure of confidential information. 

All transfers that are needed during the conduct of a clinical trial need to be pre-specified. 

Validation of transfer should  include appropriate challenging test sets and ensure that the process is available and functioning at clinical trial start (e.g. to enable ongoing sponsor review of diary data, lab data or adverse events by safety committees). Data transcribed or extracted and transferred from electronic sources and their associated audit trails should be continuously accessible (according to delegated roles and corresponding access rights). 

Transfer of source data and records where the original data or file is not maintained is a critical process and appropriate considerations are expected in order to prevent loss of data and metadata. 

6.1.3. Direct capture 

Direct data capture can be done by using electronic data input devices and applications such as electronic diaries, electronic questionnaires, and eCRFs for direct data entry. Where treatment-related pertinent information is captured first in a direct data capture tool such as a trial participant diary, a PRO form or a special questionnaire, a documented procedure should exist to transfer or transcribe information into the medical record, when relevant.

Direct data capture can be done by automated devices such as wearables or laboratory or other technical equipment (e.g. medical imaging, electrocardiography equipment) that are directly linked to a data acquisition tool. Such data should be accompanied by metadata concerning the device used (e.g. device version, device identifiers, firmware version, last calibration, data originator, time stamp of events). 

6.1.4. Edit checks 

Computerized systems should validate manual and automatic data inputs to ensure a predefined set of validation criteria is adhered to. Edit checks should be relevant for the protocol and developed and revised as needed. Edits checks should be validated and implementation of the individual edit checks should be controlled and documented. If edit checks are paused at any time during the trial, this should be documented and justified. Edit checks could be either run immediately at data entry or automatically during defined intervals (e.g. daily) or manually”. 

Clinical trials conducted in Germany must comply with the General Data Protection Regulation (GDPR) No 2016/679 and the German Federal Protection Act on the protection of natural persons with regard to the processing of personal data, which outlines clear responsibilities for organizations processing personal data.

5.6 If a clinical study involves the study product as OTC and this is provided via pharmacy/amazon, etc., are there any specific regulations for IP management that need to be followed?

The EU CTR 536/2014 does not mention OTC but instead, they are using the term of Auxiliary Medicinal Product (AMP), which is defined in Art 2 (8) as “ a medicinal product used for the needs of a clinical trial as described in the protocol, but not as investigational medicinal product”.

Art 2. (10) goes further on the AMP clarification indicating: “a medicinal product authorized in accordance with Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an auxiliary medicinal product”.

In March 2024, the EMA updated the recommendations on “Auxiliary Medicinal Products in Clinical Trials”. These recommendations can also be found in Chapter III- Quality section under the Eudralex Volume 10. This publication provides additional clarifications, such as:

“Examples are medicinal products used as rescue medication, challenge agents, to assess end-points in the clinical trial, or background treatment. Further, the medicinal product should be related to and relevant for the design of the clinical trial, which excludes ‘concomitant medications’. As outlined in preamble 54 concomitant medications is unrelated to the clinical trial and not relevant for the design of the clinical trial”. For further definition and examples, see Annex 1 of this document."

Therefore, an authorized or marketed medicinal product (i.e.: Auxiliary Medicinal Product) used in a clinical trial, will need to comply with the requirements set within the EU CTR and will be labeled accordingly.

5.7 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

National provisions do not directly address this topic.

At a European level, the purchase of study product potentially conflicts with the provisions of Annex VI of the Clinical Trial Regulation (EU) 536/2014, which provides, at C.7, in respect of authorized investigational products, that “the following particulars shall appear on the immediate and the outer packaging:

(a) name of the main contact;

(b) clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor, and subject;

(c) 'For clinical trial use only' or similar wording”.

Investigational products should be free for participants. Art 92, Clinical Trial Regulation (EU) 536/2014: 

“Investigational medicinal products, other products and procedures, free of charge for the subject.

Without prejudice to the Member States' competence for the definition of their health policy and for the organisation and delivery of health services and medical care, the costs for investigational medicinal products, auxiliary medicinal products, medical devices used for their administration and procedures specifically required by the protocol shall not be borne by the subject, unless the law of the Member State concerned provides otherwise.” 

5.8 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

Yes, but adequate compensation only.

According to Article 31(1)(d), Article 32(1)(d), and Article 33(d) of the EU CTR 536/2014, no incentives or financial inducements, other than compensation for participation in the clinical trial, are to be given to incapacitated subjects, legal representatives, minors and pregnant and breastfeeding women. This compensation should not cover more than expenses and loss of earnings, directly related to participation in the clinical trials. 

Examples of expenses directly related to the participation in the clinical trials are travel costs for the participating subject and the legally designated representative (if applicable) or (if applicable) the person accompanying the subject, costs for accommodation, or additional costs due to participation in the clinical trial collected by the subjects’ health insurance (compulsory patient contributions/own risk). 

The information on compensation shall be submitted in the application dossier (CTR Annex I, P (70)) and as such is subject to assessment. A small token of appreciation is not considered an incentive but needs to be explicitly allowed by the ethics committee.

Please refer to Question 9.1, Clinical Trial Regulation 536/2014, Q&As December 2023.

Additional information can also be found in Section 3.13 of this Guidebook.

5.9 Specific labeling requirements for clinical study product

Label requirements as indicated within Chapter X, Article 66 of the EU CTR 536/2014 are applicable.  

Labeling in the German language is necessary. Additionally, BfArM indicates on its website that labeling must comply with the requirements of Section 5 of the GCP-V Ordinance.

According to the FAQ available on the BfArM website related to "labeling": It is possible to use marketed (licensed) medicinal products in the usual market packaging and labeling as study medication without study-specific relabeling if this is in agreement with the study design. An exception to this is that if the channel of distribution (wholesale, pharmacy) is not maintained, an additional label bearing the information “for clinical trial use only” is required (Section 47 sub-section 1 number 2 letter g AMG).

5.10 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

Please refer to Section 2.6.

5.11 What is the turn-around time to get an import permit?

Please refer to Section 2.6.

5.12 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

From the research conducted, this information is not evident. It is expected that the competent RA would permit the destruction of clinical supplies at an off-site location.