BfArM recommends that a cover letter signed by the sponsor or a representative of the sponsor be submitted with each application, highlighting the specifics of the clinical investigation and referencing the relevant information in other documents. An accompanying letter should also be submitted for each subsequent submission.

The cover letters can be uploaded e.g. as other type/anderer Typ (AT) via the DIMDI database system.

Unfortunately, it is not possible to have application documents reviewed before the actual approval procedure. A binding statement as to whether the clinical investigation plan meets the requirements can therefore only be made after detailed assessment in the course of the approval procedure.

However, the BfArM offers scientific advice procedures for the pharmaceutical and medical device sectors where certain questions of content can be discussed and recommendations for further action can be given before an application is submitted. Such consultations are subject to fees.

Since 21 March 2010, in accordance with Section 20 sub-section 1 of the Medical Devices Act (MPG), clinical investigations of medical devices may only be commenced in Germany if the responsible Ethics Committee has issued a favourable opinion on the clinical investigation pursuant to Section 22 MPG and the competent federal higher authority has authorised it pursuant to Section 22a MPG. This approval procedure with the federal higher authority replaces the previous notification obligation with the authorities of the "Land". The beginning of the clinical investigation is specified as the time when the first subject has legally consented to the participation after all the prerequisites for the start of the clinical investigation have been met.

The commencement, duration, changes, completion or early termination of the clinical investigation are regulated in Sections 22a - 23a MPG.

Clinical investigation:
The authorisation required under Article 62 (4) a) MDR must be applied for by the sponsor to the competent higher federal authority, here: BfArM. In accordance with Article 70 (1) MDR, the application must be submitted by way of data transmission via the DMIDS central registration system. The application must be accompanied by the documents listed in Annex XV Chapter II MDR. The application form asks for the data that are absolutely necessary for processing the application. Required documents can also be uploaded and transmitted via the system.

Performance study:
The authorisation required under Article 58 (1) or (2) IVDR must be applied for by the sponsor to the competent higher federal authority. In accordance with Article 66 (1) IVDR, the application must be submitted by means of data transmission via the DMIDS central registration system. The application must be accompanied by the documents listed in sections 2 and 3 of Annex XIII and in Annex XIV IVDR. The application form asks for the data that are absolutely necessary for processing the application. Required documents can also be uploaded and transmitted via the system.

No. In accordance with Section 44 sub-section 4 of the Medical Devices Act (MPG), Sections 19 to 24 of the Medical Devices Act (MPG) as amended by the announcement of 7 August 2002 (German Federal Law Gazette I p. 3146), last amended by Article 1 of the Law of 14 June 2007 (German Federal Law Gazette I p. 1066) continue to apply for clinical investigations and performance studies started before 21 March 2010.

A clinical investigation according to MDR is considered to have started ("initiated") as soon as the required approval of the higher federal authority and the consenting assessment of the ethics committee have been obtained.

A performance study according to the IVDR, on the other hand, is only considered to have begun as soon as the first subject or patient has given legally valid consent to the trial after all prerequisites for the start of the trial have been met.

These are not clinical trials or performance studies requiring approval according to the MDR or the IVDR if the medical device is used exclusively within the scope of its intended purpose (strictly according to the instructions for use, incl. indications, contraindications, etc.) and no additional invasive or stressful examinations are carried out. In general, however, professional guidelines for the physicians involved must be observed and an appropriate ethics committee must be involved.

No.

No. According to Article 62 (2) and (4) (c) MDR or Article 58 (4) and (5) (c) IVDR, the sponsor, if not established in the Union, must appoint a legal representative in the Union. Neither Switzerland nor Turkey is a member of the EU or a contracting state of the EEA.

We recommend that a tabular list be drawn up, arranged in the rows following the Essential Safety and Performance Requirements set out in Annex I to Regulation (EU) 2017/745 (MDR) or Annex I to Regulation (EU) 2017/746 (IVDR). The list should contain further columns on the following information for each Essential Requirement: The indication whether the corresponding requirement is applicable or not, the indication of the standards or Common Technical Specifications applied in full or in part, and a description of the solutions to comply with the requirements if these standards have not been complied with or are missing. In another column of the list, we recommend indicating the relevant reference documents (e. g. documents from testing laboratories). These documents should be clearly identifiable (name, date, version number) and refer to the technical documentation. Templates for these lists can also be found on the internet.

The sponsor must submit an evaluation and assessment of the foreseeable risks, disadvantages and distress for the trial subject weighed against the prospective significance of the medical device for medical science and the anticipated benefit for the trial subject.

Please note that both the risks, disadvantages and stress arising from participation in the clinical investigation / performance study as well as the risks emanating from the medical device itself are to be described.

A risk evaluation should include an estimation of the severity and the probability of occurrence.

The overall residual risk must be compared with the benefit for the trial subject as a result from his/her participation in the clinical investigation / performance study as well as with the benefit for medical science.

In the end, the sponsor must weigh the risks presented against the benefits presented in a comprehensive discussion and must conclude with a final evaluation.

In the case of an application for authorisation of a clinical investigation under the MDR or a performance study under the IVDR, a power of attorney for the legal representative of the sponsor in the Union (cf. Article 62 (2) and (4) (c) MDR or Article 58 (4) and (5) (c) IVDR) must be submitted if the sponsor itself is not established in the Union. It is recommended to submit a power of attorney signed by the sponsor and its legal representative, demonstrating that the representative is aware of its mandate and that the appropriate contractual agreements with the sponsor exist for this purpose.

If a third party (e. g. a CRO) is involved who is to take over the communication, a power of attorney must also be submitted for this party.

In accordance with Section 3 sub-sections 2 and 4 as well as with Section 7 sub-section 2 of the Ordinance on Clinical Investigations of Medical Devices (MPKPV), the requirements for the documents to be submitted remain the same even if a new application is submitted for the same medical device.

However, it is advisable to refer to the previous clinical investigation in a cover letter which should allow a clear identification of that clinical investigation (BfArM reference number, title of the clinical investigation).

Please bear in mind that that the results of previous clinical investigations and, if applicable, of corresponding interim reports must be submitted in such cases.

Please note that since 26.05.2021 this only applies to subsequent changes in performance studies of in vitro diagnostics.

In the case of notified "other changes", the competent higher federal authority (here: BfArM) may determine that the notified change fulfils the requirements of a substantial change. The BfArM informs the sponsor of this without delay by means of the notice "Determination of Substantiality" (Section 8 (1) sentence 3 MPKPV).

The sponsor is thus requested to resubmit an application for assessment of a substantial modification via the DMIDS for the previously notified modification.

Yes, since substantial amendments include all amendments that affect the other requirements assessed by the Ethics Committee.

For a substantial modification, an application for assessment must be submitted to the competent higher federal authority and for evaluation to the competent ethics committee. In its current practice, the BfArM only takes note of substantial changes that exclusively affect the requirements of the Ethics Committee.

For clinical investigations initiated before 26.05.2021 and for performance studies initiated before 26.05.2022, the provisions of Section 23a MPG apply. Within 90 days after termination of a clinical investigation, the sponsor must notify the competent higher federal authority (here: BfArM) of the termination of the clinical investigation.

If the clinical investigation is discontinued, this period is reduced to 15 days. The notification must state all reasons for the discontinuation. Receipt of the notification is confirmed by the BfArM.

The sponsor submits the final report to the competent higher federal authority within twelve months of discontinuation or completion of the clinical trial. Receipt of the report is also confirmed by the BfArM.

It is recommended that the content of the final report be based on Annex D of the standard DIN EN ISO 14155:2020. For performance studies of in vitro diagnostic medical devices, the final report may also be prepared according to Annex D of ISO 20916:2019.

In Germany, the legislation provides for a cut-off date for the transition to the new legislation for clinical investigations of medical devices. This means that all applications must be submitted and processed according to the legislation valid until then (MPG and associated laws) until Regulation (EU) 2017/745 (MDR) and the Medizinprodukterecht-Durchführungsgesetz (MPDG) come into effect on 26 May 2021. From that date onwards, the MDR with the supplementary national legislation (MPDG) will immediately and exclusively be the basis for submissions and assessments. Until the start of the application of the MDR, the documents submitted in the context of an application for authorisation of a clinical investigation must therefore comply with the requirements of the applicable legislation (MDD 93/42 / EEC, MPG); from then on, they must comply with the legislation applicable with the start of the validity of the MDR.

All clinical investigations that are not considered initiated in the sense of the law (§ 99 MPDG) on the cut-off date must be reapplied for and reassessed according to the new legislation; a continuation or even a completion of the assessment on the basis of the previously submitted application documents is not possible for legal reasons.

In Germany, a clinical investigation of a medical device is considered to have been initiated if it has already been approved by the competent authority on the cut-off date (currently 26.05.2021) and the favourable opinion of the ethics committee(s) has also been obtained (Section 99 (3) MPDG). If one of the two conditions is not met, a new application is required in accordance with the MDR requirements.

Clinical investigations which, according to current legislation, do not require approval by the competent authority before 26.05.2021 are deemed to have been initiated within the meaning of the law if the first subject has declared his or her consent to participate before the cut-off date (Section 99 (4) MPDG).

Clinical investigations that are considered already initiated on the cut-off date may be continued on the basis of the legislation in force before the cut-off date.

The cut-off date regulation is laid down in § 99 Para. 3 ff. of the MPDG.

It should also be noted that the application procedure is sequential from the date of application of the MDR in Germany: First, the application must be submitted to the ethics committee, and only then can the application for the clinical investigation be submitted to the federal higher authorities. From the beginning of the MDR / MPDG, the application documents must be accompanied by the favourable opinion of the ethics committee.

A preliminary remark:

In order to avoid misunderstandings, it should be noted that the term "other clinical investigation", which has been used in practice up to now, is not legally defined. As a rule, this refers to clinical investigations of medical devices that require the consultation of an ethics committee in accordance with the medical professional code of conduct (“ärztliche Berufsordnung”), but are not subject to an approval procedure under medical device law. In addition to clinical investigations which fulfil the criteria according to § 23b MPG, this also includes clinical investigations which are carried out, for example, for fundamental research questions for purely scientific reasons.

A distinction must be made between these and the term "other clinical investigation" introduced by Article 82 MDR, which is defined by Section 3 No. 4 of the MPDG in Germany. It includes clinical investigations that are conducted to answer purely scientific questions and that are not conducted as part of a conformity assessment procedure, a planned product development or a development plan (according to Annex XIV Part A No. 1 letter a of the MDR) for a medical device.

What is a PMCF investigation?

A PMCF (Post Market Clinical Follow-up) investigation in the sense of the MDR is understood to be a clinical study with a medical device after it has been placed on the market. The investigational device is used in accordance with its intended purpose as defined for the CE mark. The purpose of the investigation is to systematically collect clinical data for the purpose of evaluating the safety and/or performance of a device (see Article 2 No. 45 of the MDR).

PMCF investigation without additional invasive or burdensome procedures in the context of the MDR and the MPDG:

For these clinical investigations, there is neither an obligation to notify nor an obligation to obtain approval from the ethics committee or the federal higher authorities. However, the obligation of consultation according to professional law for physicians (see § 15 of the respective professional regulations (“ärztliche Berufsordnung”)) by the ethics committees remains unchanged.

Serious adverse events (SAEs) do not have to be reported to the federal higher authorities; the vigilance provisions remain valid without restriction.

The handling in Germany thus corresponds to the former regulation in the MPG for clinical investigations which fulfil the criteria according to § 23b MPG.

Other clinical investigation according to Article 82 MDR with a device after it has been placed on the market, which is used in the context of its intended purpose and in which the subjects are not exposed to any additional invasive or burdensome procedures:

Section 47, paragraph 3 of the MPDG suspends the requirements of paragraphs 1 and 2 of the same section. This includes the necessity of a favourable opinion by the ethics committee and the obligation to notify the federal higher authorities.

The incident reporting obligations are to be observed. The obligation to report serious adverse events (SAEs) is abolished by Section 64, paragraph 4 of the MPDG for these clinical investigations. However, obligations arising from the professional code of conduct for physicians (“ärztliche Berufsordnung”), e. g. consultation according to professional law when participating in research projects, remain unaffected.

If applicable, further provisions resulting from other legal requirements must be taken into account when conducting the clinical investigation.

Information on SAE and DD reporting requirements can be found in the Applications and Reports section.

In the European Regulation 2017/746 (IVDR), there is no guidance on performance studies for the transition from the In Vitro Diagnostics Directive (IVDD, 98/79/EC) to the IVDR. However, the German Medical Devices Implementation Act (“Medizinprodukterecht-Durchführungsgesetz”, MPDG) contains a corresponding passage in § 100 paragraph 3:

(3) Performance evaluation studies pursuant to Section 24 of the Medical Devices Act in the version applicable up to and including 25 May 2020 that were commenced before 26 May 2022 may continue to be conducted as performance studies pursuant to Article 2(42) of Regulation (EU) 2017/746 on the basis of the provisions applicable to them up to and including 25 May 2022.

A performance evaluation study shall be deemed to have commenced within the meaning of sentence 1 if, after all requirements for the commencement of the performance evaluation study have been met, the first subject has consented to participate in the performance evaluation study.

It should be noted that performance studies subject to application under the MPDG are not considered to have started as soon as authorisation has been obtained from the competent ethics committee and the competent federal higher authority. In all cases, a performance study is only considered to have commenced within the meaning of Section 100(3) MPDG if the first subject has agreed to participate in the study by 25.05.2022 (inclusive).

Performance studies for which this condition is not fulfilled may have to be re-authorised according to the new legal framework (IVDR and MPDG).

The SAE reporting obligations must continue to be carried out in accordance with the Medical Devices Safety Plan Ordinance (“Medizinprodukte-Sicherheitsplanverordnung”, MPSV) for performance studies that are deemed to have commenced within the meaning of Section 100(3) of the MDPG, even after the IVDR becomes applicable.

The provided decision tree serves as a guide as to which performance studies are subject to approval or notification. The information from Chapter VI of the IVDR and Chapter 4 of the MPDG is decisive.

If there is a need for clarification, the BfArM decides in accordance with § 6 paragraph 3 MPDG, upon application by a competent authority or a sponsor, whether a performance study subject to approval is involved

The application for a decision on whether a performance study requires approval must be submitted independently of an application for approval according to Section 38 MPDG.

In Germany, the competent higher federal authorities are responsible for notifications of or applications for approval of performance studies with companion diagnostics (CDx). This is either the Paul Ehrlich Institute (PEI) or the Federal Institute for Drugs and Medical Devices (BfArM). To which of the two competent higher federal authorities the notification or application is to be addressed depends on the responsibility for the associated medicinal product:

According to Section 85 Paragraph 3 No. 2 MPDG, the competent higher federal authority (PEI or BfArM) is responsible for the approval of a performance study with a companion diagnostic intended for the safe and effective use of an associated medicinal product, which is also responsible for the associated medicinal product according to the Medicinal Products Act.

This question cannot be answered in a blanket manner, but depends on the individual conditions in each case. Information on this can be found on the website of the working group of ethics committees that advise on this question.

The MPDG defines the term "residual sample" as residual material of human body substances that originates from a medically indicated collection (§ 3, MPDG).

The IVDR does not define the terms. The MDR defines an invasive device as a device that enters the body, in whole or in part, through the surface of the body or through a body orifice (Article 2, 6 MDR). A surgically invasive device is an invasive device that enters the body through the body surface - including the mucous membranes of body orifices - by means of or in connection with a surgical intervention, and a device that enters the body other than through a body orifice (Annex VIII, Chapter I, 2.2, MDR).

If there is uncertainty as to whether the procedure is an additional invasive procedure or whether there are other risks to the trial subjects, the ethics committee can provide advice.
Further information from AKEK

Alternatively, a decision can be obtained from the BfArM on application to clarify the question of whether it is a performance study requiring approval.

As soon as a part of the performance study (such as recruitment, sample collection or application of the IVD) takes place in Germany, it must be checked whether the study is subject to a notification or authorisation requirement. The provided decision tree serves as an initial orientation as to which procedure is to be applied. The information from Chapter VI IVDR and Chapter 4 MPDG are decisive.

The necessary qualifications of the investigators are checked by the ethics committee when the application is submitted. Further information can be found on the AKEK website.

The IVDR refers to "devices manufactured and used exclusively within healthcare facilities established in the Union" (Article 5(5) IVDR). A "healthcare establishment" is defined in the IVDR as an organisation whose primary purpose is the care or treatment of patients or the promotion of public health (Article 2 IVDR).

The conditions to be fulfilled by health care facilities are also regulated in Article 5, paragraph 5 of the IVDR. In Germany, the respective state authorities are responsible for the supervision of health care facilities.
Overview of the competent authorities of the "Länder" in Germany

Information on SAE and DD reporting requirements can be found in the Applications and Reports section.