Performance studies conducted in accordance with Article 58(1)(b) or (c) of Regulation (EU) 2017/746 (IVDR) require the approval of the competent higher federal authority in accordance with Article 58(5)(a) of the IVDR in the version applicable from 26 May 2022 in conjunction with Section 31a(2) of the MPDG. These performance studies include performance studies in which…

• it is an interventional clinical performance study as defined in point (46) of Article 2
• the conduct of the study involves additional invasive procedures or other risks for the subjects of the study
• surgically invasive sample-taking is done only for the purpose of the performance study and where the specimen collection represents a major clinical risk to the subject of the study.

To initiate the approval procedure for performance studies, an application must be submitted to the competent higher federal authority. This publication provides further information on the documents to be submitted. This specification is based on the legal regulations valid from 26 May 2022, the normative requirements and the European directives as well as on the national legislation (“Medizinprodukterecht-Durchführungsgesetz”, MPDG). The aim of the publication is to enable a valid application and thus an effective approval procedure.

The following information is without prejudice to the obligation of an applicant to submit further documents not listed here as part of an application for a favourable opinion to the Ethics Committee. Details of the documents to be submitted for the Ethics Committee can be found on the website of the Association of Medical Ethics Committees in Germany (“Arbeitskreis Medizinischer Ethik-Kommissionen”, AKEK).

The requirements for the sponsor and the review mandate for the higher federal authorities in the authorisation procedure are described in Articles 58 and 66 f. IVDR as well as in its Annex XIV.

The authorisation required under Article 66(7)(b) IVDR in conjunction with Section 31a(2) MPDG must be applied for by the sponsor to the competent higher federal authority (Paul Ehrlich Institute or Federal Ministry for Drugs and Medical Devices). The application shall be submitted via the electronic system pursuant to Article 69 IVDR (EUDAMED).

As long as the central European database EUDAMED does not provide the corresponding functionality, the application is submitted via the German Medical Devices Information and Database System (“Deutsche Medizinprodukte-Informations- und Datenbanksystem”, DMIDS) of the Federal Institute for Drugs and Medical Devices (BfArM). The DMIDS application form asks for the data required to process the application.

In addition to the information specified in the DMIDS application form, the submission must be accompanied by the following documents, if applicable in the individual case, in German or, unless otherwise specified, in English (cf. sections 2 and 3 of Annex XIII and in Annex XIV IVDR):

1. Application form
   (Contents see Annex XIV, will be requested accordingly in the electronic application form (EUDAMED or DMIDS)).
2. Investigator's brochure
3. Performance study plan as referred to in Sections 2 and 3 of Annex XIII
4. Other information

Note on the investigator's brochure and the performance study plan:

Annexes XIII and XIV of the IVDR describe further information on the content of the documents. In addition, it is recommended that the current version of the standard DIN (EN) ISO 20916 be used as a guideline.

Information on points that were previously contained in separate documents (e. g. technical documentation, risk analysis, etc.) must now be presented more carefully in the performance study plan or in the investigator's brochure. Reference to other applicable documents is possible. These must be clearly referenced and submitted.

Other information (Section 4 of Annex XIV to the IVDR):

1. Signed statement by the manufacturer that the device for performance study in question to the general safety and performance requirements apart from the aspects covered by the clinical performance study and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject.
2. Copy of the opinion of the ethics committee
3. Proof of subject insurance coverage
4. Documents to be used to obtain informed consent
5. Information on the protection and confidentiality of personal data
6. If requested by the competent authority, full details of the available technical documentation, e. g. risk analysis/management or specific test reports.

Please note that with the start of application of the IVDR, a sequential application procedure was also introduced for performance studies in Germany. This means that the application must first be submitted to the competent ethics committee and can only then be forwarded by the sponsor to the competent higher federal authorities. According to § 38 MPDG, the statement of the competent ethics committee must be attached to the application to the higher federal authority.

It is pointed out that additional applications for approval according to the relevant regulations of the Medicines Act, the X-ray Ordinance or the Radiation Protection Ordinance may be necessary. A detailed discussion of the statistical interpretation and significance that are the subject of the study design is necessary.

The assessment and justification of the risks associated with the performance study for the person involved in it, measured against the anticipated importance of the product for medical science, should be presented in a reasoned manner. The alternative ways of gaining knowledge, lower-risk alternatives and the current state of the art used for comparison should be described in detail.

Should follow-up be required, appropriate medical care and follow-up of subjects shall also be provided in cases of suspension or early termination of the performance study. The process of follow-up of subjects may require the need for immediate delivery and decoding of parts of the cohort. Consideration shall be given to the possibility of continuing the investigation for those parts of the trial affected or unaffected by a corrective measure.

The procedure for the reporting and self-responsible investigation of serious adverse events (SAEs) and device deficiencies (DDs) must describe and ensure the implementation of the regulatory requirements at European and national level (see Medical Device Law Implementation Act). The use of the reporting form for SAEs and DDs published by the BfArM by the sponsor shall be ensured until the availability of the corresponding functionality in EUDAMED. The system of reporting shall ensure a clear assignment of the SAE and device deficiency report to the investigation and the trial site.

The risk analysis and assessment should take into account the procedures of the relevant harmonised standard and shall be kept up to date during the performance study. This shall be particularly considered in the assessments of SAEs / DDs and the implementation of corrective measures.

Procedure at the higher federal authority:

The authority must first validate the application within 10 days by verifying that the performance study applied for falls within the scope of the IVDR and that the application documents are complete. If it finds that this is not the case, it notifies the applicant and requests him to modify the application within 10 days. If necessary, the higher federal authority may extend this deadline by a maximum of 20 days. A corresponding extension can be requested informally by e-mail. Where the sponsor has not provided comments nor completed the application within the time limit, the application shall be deemed to have lapsed (rejected).

The authority shall notify the sponsor within five days of receipt of the comments or of the requested missing documents, whether the performance study is considered as falling within the scope of this Regulation and the application is complete. The Authority may extend the periods to it by a further five days. It should be noted that the 45-day period referred to in Article 66(7)(b) of the IVDR does not start until a proper application (date of validation) has been submitted.

During the period when the application is being assessed the Member State may request additional information from the sponsor. The expiry of the deadline shall be suspended from the date of the first request until such time as the additional information has been received (Article 66(6) IVDR).

Prior to submitting an application, it is possible to contact the BfArM at the email address medizinprodukte@bfarm.de and receive scientific advice from the BfArM. Please refer to the information on the BfArM homepage for scientific advice.

The choice of the abridged application procedure according to Article 66(7)(a) IVDR in conjunction with Section 31a(1) MPDG is possible for performance studies in which samples are collected in a surgically invasive manner exclusively for the performance study, but where the specimen collection does not represent a major clinical risk to the subject of the study.

However, this must not at the same time be an interventional clinical performance study within the meaning of Article 2 No. 46 IVDR and there must be no other additional invasive procedures or other risks for the subjects of the study.

If the following criteria are met, the abridged application procedure for a performance study may be chosen in Germany:

• surgically invasive sample collection for performance study only
• surgically invasive sample collection does not pose a significant risk to subjects
• it is not an interventional clinical performance study
• subjects will not be exposed to additional invasive procedures or other risks

The application for the abridged procedure for the approval of a performance study must be submitted in German or English by the sponsor to the competent higher federal authority (either the Paul Ehrlich Institute or the Federal Institute for Drugs and Medical Devices) via the electronic German Medical Devices Information and Database System (”Deutsche Medizinprodukte-Informations- und Datenbanksystem”, DMIDS) as long as the European database EUDAMED is not available for this purpose.

Please note that Germany introduced a sequential application procedure when the IVDR came into application. The application must first be submitted to the competent ethics committee via the DMIDS and can only be forwarded to the competent higher federal authority after receiving their favourable opinion.

Documents to be submitted:

1. All documents listed in Annex XIV IVDR.
2. The favourable opinion of the Ethics Committee.

Information on the documents to be added for the Ethics Committee can be found on the website of the Association of Medical Ethics Committees in Germany (“Arbeitskreis Medizinischer Ethik-Kommissionen”, AKEK).

Procedure at the higher federal authority:

The authority must first validate the application within 10 days by verifying that the performance study applied for falls within the scope of the IVDR and that the application documents are complete. If it finds that this is not the case, it notifies the applicant and requests him to modify the application within 10 days. If necessary, the higher federal authority may extend this deadline by a maximum of 20 days. A corresponding extension can be requested informally by e-mail. Where the sponsor has not provided comments nor completed the application within the time limit, the application shall be deemed to have lapsed (rejected).

The authority shall notify the sponsor within five days of receipt of the comments or of the requested missing documents, whether the performance study is considered as falling within the scope of this Regulation and the application is complete. The Authority may extend the periods to it by a further five days. It should be noted that the 45-day period referred to in Article 66(7)(b) of the IVDR does not start until a proper application (date of validation) has been submitted.

Please note that at this point Germany has made use of the possibility to define more extensive requirements compared to the IVDR:

Once it has been established that the application is valid (the application falls within the scope of the IVDR, the document has been submitted in full), the competent higher federal authority must, in accordance with Section 31a(1) and Section 39(4) of the MPDG, assess within 10 days of the validation date whether the specimen collection presents a major clinical risk to the subject of the study. Should the specimen collection presents a major clinical risk to the subject of the study, the competent higher federal authority shall object to the commencement of the performance study.

The sponsor may commence the performance study if the higher federal authority has not objected to the application within 10 days of the validation date and if the ethics committee responsible in accordance with Section 33(1) MPDG has issued a favourable opinion in this regard.

Please note that the foregoing does not apply to in vitro diagnostic devices intended solely for research purposes but not specifically for in vitro investigations. Performance studies with products manufactured and used in-house are also not covered by this regulation.