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Request for authorisation of a clinical investigation

2022.08.17

Clinical investigations of medical devices that are conducted as part of the clinical evaluation for conformity assessment purposes and where the investigational device either may not yet bear a CE mark or its use in the clinical investigation is outside its intended purpose require approval by the competent federal higher authority.

Legal Basis

The obligation to obtain an authorisation from the competent authority in the respective Member State of the European Union arises from Article 62(4) point a of Regulation (EU) 2017/745 (MDR):

„(a) the clinical investigation is the subject of an authorisation by the Member State(s) in which the clinical investigation is to be conducted, in accordance with this Regulation, unless otherwise stated;“

Application and authorisation procedure

According to Article 70 MDR, an application for authorisation of a clinical investigation must be submitted via the electronic system pursuant to Article 73 MDR. 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 (DMIDS) of the Federal Institute for Drugs and Medical Devices (BfArM). With the start of application of the MDR, a sequential approval procedure was introduced in Germany: The application must first be forwarded to the competent ethics committee and can only be transmitted to the competent federal higher authority after its approval (all via DMIDS).

The application process, including the procedure and deadlines at the authority, is described in more detail in Article 70 MDR and can be split into a validation phase and a substantive review phase. During the validation of an application, the authority ensures that the application falls within the scope of the MDR and that all required documents have been provided by the sponsor (see Article 70(2)-(5) MDR). This validation phase is identical for all applications submitted to the federal higher authority for authorisation of a clinical investigation according to MDR. The subsequent substantive review of the application differs according to the regulatory classification of the investigational device in accordance with Article 70(7) MDR in conjunction with Section 31 of the Medical Device Law Implementation Act (“Medizinprodukterecht-Durchführungsgesetz”, MPDG).

It should be noted in particular that Germany has made use of the option to define deviating national regulations:

㤠31 Commencement of a Clinical Investigation

(1) A clinical investigation of devices classified as class I in accordance with the classification rules laid down in Chapter III of Annex VIII to Regulation (EU) 2017/745 or of non-invasive devices classified as class IIa in accordance with the classification rules laid down in Chapter III of Annex VIII to Regulation (EU) 2017/745 may only be commenced after

1. the competent federal higher authority has not objected within ten days of the validation date in accordance with Article 70(5) of Regulation (EU) 2017/745; and
2. the competent ethics committee pursuant to Article 33(1) has issued a favourable opinion in this regard.

(2) A clinical investigation of devices other than those referred to in paragraph 1 may only be commenced if

1. he competent federal higher authority has granted approval for this purpose, and
2. the competent ethics committee pursuant to Section 33 paragraph 1 has issued a favourable opinion in this regard.“

The following should be noted:

In Germany, in deviation from the requirements of the MDR, the full authorisation procedure according to Article 70(7) point b MDR and not the abridged authorisation procedure according to Article 70(7) point a MDR must be chosen for investigational devices that are assigned to class IIb according to the classification rules of Annex VIII Chapter III of Regulation (EU) 2017/745. This therefore also applies to non-invasive investigational devices of risk class IIb.

Furthermore, contrary to the wording in the MDR, in the case of investigational devices of risk class I and non-invasive IIa (abridged authorisation procedure), the clinical investigation may not be started immediately after the date of validation. According to Section 39(3) MPDG, the competent federal higher authority must, according to Section 31(1) MPDG (see above, abbreviated application procedure), check within 10 days from the date of validation "...whether the classification rules of Annex VIII of Regulation (EU) 2017/745 have been applied correctly."

Full authorisation procedure

Application for Authorisation of a Clinical Investigation Pursuant to Article 70(7)(b) of Regulation (EU) 2017/745 in Conjunction with the Medical Devices Law Implementation Act (MPDG) at the Federal Institute for Drugs and Medical Devices (BfArM) - Full Authorisation Procedure

The conduction of clinical investigations of medical devices that are assigned to risk class invasive IIa, IIb or III according to the classification rules of Annex VIII Chapter III of Regulation (EU) 2017/745 (MDR) requires the approval of the competent federal higher authority pursuant to Article 62(4) point (a) MDR in conjunction with Section 31(2) Number 1 of the Medical Devices Law Implementation Act (“Medizinprodukterecht-Durchführungsgesetz”, MPDG).

To initiate the approval procedure for clinical investigations of medical devices, an application must be submitted to the competent federal higher authority. This publication provides further information on the documents to be submitted. This information is based on the legal regulations applicable as of 26 May 2021, the normative requirements and the European directives, as well as on the MPDG applicable as of 26 May 2021. The aim of the publication is to enable a correct 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 from the ethics committee.

The requirements for the sponsor and the assessment mandate for the federal higher authorities in the authorisation procedure are described in Articles 62 and 70f. MDR as well as in its Annex XV.

The authorisation required under Article 70(7) point b of the MDR in conjunction with Section 31(2) Number 1 of the MPDG must be applied for by the sponsor to the competent federal higher authority. The application pursuant to Article 70 MDR shall be submitted by way of data transmission via the electronic system pursuant to Article 73 MDR (EUDAMED) in accordance with Article 70(1) MDR.

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 (DMIDS, formerly DIMDI) of the Federal Institute for Drugs and Medical Devices (BfArM). The DMIDS application form asks for the data that are absolutely necessary for processing the application.

In addition to the information specified in the DMIDS application form, the application must be accompanied by the following documents in German or, unless otherwise specified, in English, as applicable in the individual case (cf. Annex XV, Chapter II MDR):

  1. Application Form
    (Contents see Annex VX MDR, are requested accordingly in the electronic application form (EUDAMED or DMIDS)).
  2. Investigator's Brochure
  3. Clinical Investigation Plan
  4. Other information

Comment on the Investigator's Brochure and the Clinical Investigation Plan:

Annex XV of the MDR describes further information on the content of the documents. In addition, it is recommended to follow the DIN (EN) ISO 14155 standard in its current version.

Information on points that were previously contained in separate documents (e.g. technical documentation, risk analysis, etc.) must now be presented more carefully in PP and IB. Reference to other relevant documents is possible. These must be clearly referenced and also submitted.

Other information (Annex XV, Chapter II, Section 4 of the MDR):

  1. A signed statement by the natural or legal person responsible for the manufacture of the investigational device that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigation 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 or opinions of the ethics committee or committees concerned
  3. Proof of insurance cover or indemnification of subjects in case of injury, pursuant to Article 69 and the corresponding national law.
  4. Documents to be used to obtain informed consent, including the patient information sheet and the informed consent document.
  5. Description of the arrangements to comply with the applicable rules on the protection and confidentiality of personal data.
  6. Full details of the available technical documentation, for example detailed risk analysis/management documentation or specific test reports, shall, upon request, be submitted to the competent authority reviewing an application.

Please note that a sequential application procedure was introduced in Germany when the MDR and the MPDG came into effect. The application must first be submitted to the competent ethics committee and can only then be forwarded by the sponsor to the competent federal higher authorities. The application to the federal higher authorities must be accompanied by the opinion of the competent ethics committee in accordance with Section 38 of the MPDG.

It is pointed out that additional applications for approval according to the relevant regulations of the Medicines Act, 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 clinical investigation for the subject in whom it is to be conducted, measured against the anticipated relevance of the medical device to the medical profession, 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 reference should be described in detail.

Follow-up care must also ensure adequate medical care and support for the subjects in cases of suspension or premature termination of the investigation. This is particularly important for investigations of implants. The process of follow-up of subjects in the investigation may require the need for immediate delivery and decoding of subsets of the subject population. Consideration should be given to the possibility of continuing the investigation for those parts of the investigation that are or are not affected by a corrective measure.

The procedure for the reporting and investigating serious adverse events (SAEs) and device deficiencies (DDs) on one's own responsibility must describe and ensure the implementation of the regulatory requirements at European and national level (see MPDG). 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 clinical investigation. This shall be particularly considered in the assessments of SAEs / DDs and the implementation of corrective actions.

The BfArM will confirm receipt of the application in accordance with the regulations within 10 days, stating the date of validation. It should be noted that the 45-day period referred to in Article 70(7) point (b) of the MDR does not start until a valid application (date of validation) has been received.

During the period of substantive assessment of the application, the federal higher authorities may request additional information from the sponsor (Article 70(6) MDR). In the event of a request for additional information, the expiry of the time limit pursuant to Article 70(7) point (b) shall be suspended from the date of the request until receipt of the additional information (clock stop).

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

Abridged authorisation procedure

Application for an abridged authorisation procedure pursuant to Article 70(7)(a) of Regulation (EU) 2017/745 in conjunction with the Medical Devices Law Implementation Act (MPDG) at the Federal Institute for Drugs and Medical Devices (BfArM)

From the date of application of Regulation (EU) 2017/745 (MDR) and the Medical Devices Law Implementation Act (“Medizinprodukterecht-Durchführungsgesetz”, MPDG) on 26.05.2021, the BfArM will apply the following principles. The aim of this publication is to enable a correct application and thus an effective administrative procedure.

For medical devices that are assigned to class I or non-invasive IIa according to the classification rules of Annex VIII Chapter III of Regulation (EU) 2017/745 (MDR), an abridged application procedure is possible according to Article 70(7)(a) MDR and Section 31(1) MPDG. In contrast, for all other medical devices assigned to risk classes IIa invasive, IIb, as well as risk class III, a full application procedure pursuant to Article 70(7)(b) MDR is required from the competent federal higher authority.

In Germany, the abridged application procedure can be chosen for the following medical devices:

  • Risk class I
  • Risk class IIa, non-invasive

Please note that at this point Germany has made use of the possibility to specify national legal requirements deviating from the MDR: in Germany, the full application procedure according to Article 70(7)(b) MDR in conjunction with Section 31(2) MPGD must also be applied for an invasive medical device of risk class IIa.

To initiate the abbreviated application procedure for a clinical investigation, an application in German or English must be submitted by the sponsor to the BfArM via the electronic German Medical Devices Information and Database System (DMIDS) as long as the European database EUDAMED is not available for this purpose.

The following documents must be included with the application:

  1. All documents as required by Annex XV Chapter II MDR.
  2. The favourable opinion of the Ethics Committee(s)

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

Once it has been established that the application has been submitted in full to the federal higher authority, the authority must check, in accordance with Section 31(1) MPDG and Section 39(3) MPDG, whether the classification rules of Annex VIII MDR have been applied correctly and whether the risk class allows the choice of the abridged application procedure (see above).

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