Other clinical investigations "are governed by the legal basis laid down in Article 82 of Regulation (EU) 2017/745 (MDR), which is further elaborated at national level by the Medical Device Law Implementation Act (“Medizinprodukterecht-Durchführungsgesetz”, MPDG)".

The MDR describes other investigations in Article 82 as follows:

Article 82

Requirements regarding other clinical investigations

(1) Clinical investigations, not performed pursuant to any of the purposes listed in Article 62(1), shall comply with the provisions of Article 62 (2) and (3), points (b), (c), (d), (f), (h), and (l) of Article 62(4) and Article 62(6).

(2) In order to protect the rights, safety, dignity and well-being of subjects and the scientific and ethical integrity of clinical investigations not performed for any of the purposes listed in Article 62(1), each Member State shall define any additional requirements for such investigations, as appropriate for each Member State concerned.

According to Article 82(2) MDR, it is therefore up to the Member States to define the regulations for other clinical investigations themselves. Germany has made use of this possibility and defined the term "other clinical investigations" in Section 3 Number 4 of the Medical Devices Law Implementation Act (MPDG) as follows:

"Other clinical investigation" of a device of a clinical investigation that

a) is not part of a systematic and planned device development or device surveillance process of a current or future manufacturer,

b) is not carried out with the aim of demonstrating the conformity of a device with the requirements of Regulation (EU) 2017/745,

c) serves to answer scientific or other questions; and

d) is conducted outside a clinical development plan referred to in point 1(a) of Part A of Annex XIV to Regulation (EU) 2017/745.

Article 62(1) defines the purposes referred to in Article 82 as follows:

(…) as part of the clinical evaluation for conformity assessment purposes, for one or more of the following purposes:

a) to establish and verify that, under normal conditions of use, a device is designed, manufactured and packaged in such a way that it is suitable for one or more of the specific purposes listed in point (1) of Article 2, and achieves the performance intended as specified by its manufacturer;

b) to establish and verify the clinical benefits of a device as specified by its manufacturer;

c) to establish and verify the clinical safety of the device and to determine any undesirable side-effects, under normal conditions of use of the device, and assess whether they constitute acceptable risks when weighed against the benefits to be achieved by the device.

It is therefore essential to determine whether a clinical investigation is to be part of a conformity assessment procedure (including future ones) to be carried out by the manufacturer. If a clinical investigation is not intended to be part of a conformity assessment procedure to be carried out by the manufacturer, it is an "other clinical investigation" in the sense of the MDR, for which the following applies.

Furthermore, the MPDG defines the national procedures for assessment by the competent federal higher authority and the compentent ethics committees, insofar as those are not specified in the MDR, and introduces some additional conditions.

The legal requirements for the start of any other clinical investigation in Germany are defined by Section 47(2) MPDG:

An „other clinical investigation“ may only be commenced if

1. a positive opinion has been issued by the competent ethics committee in accordance with Section 52(1) MPDG, and
2. the other clinical investigation has been notified to the competent federal higher authority in accordance with Section 53(1) MPDG.

Please also note the exception to these requirements according to Section 47(3) MPDG (see below).

Notification to the Federal Higher Authority

In accordance with Section 53 MPDG, the sponsor must notify the competent federal higher authority of any other clinical investigation in accordance with Section 47(2) Number 2 via the German Medical Devices Information and Database System in accordance with Section 86 MPDG. The notification to the federal higher authority must be accompanied by a copy of the approving vote of the competent ethics committee according to Section 52(1) MPDG (see Annex XV Chapter II 4.2 MDR in conjunction with Section 47(2) Number 1 MPDG). This means that the application procedure with the competent ethics committee must be completed before the notification to the federal higher authority. It should be noted that the procedures at the ethics committee according to Sections 48 ff. MPDG must be followed.

• The notification to the federal higher authority shall contain the identification number pursuant to Section 48(3) MPDG and the information and documents referred to in Annex XV Chapter II of Regulation (EU) 2017/745, with the exception of the information and documents referred to in Annex XV Chapter II of item 1.5., 3.1.1., 4.3., 4.4. and 4.5. of Regulation (EU) 2017/745.
• Documents intended for the subject or his legal or corporate representative must be submitted in German. The other information and documents may be submitted in German or English.

Procedure of Substantial Amendments

In accordance with Section 54(1) MPDG, the sponsor must immediately notify the competent federal higher authority and the competent ethics committee of any modifications to the documents submitted in accordance with Section 48(2) and Section 53(2) MPDG via the German Medical Devices Information and Database System in accordance with Section 86 MPDG. With the notification, the sponsor shall provide an updated version of the relevant information and documentation and clearly identify the modifications in updated documentation.

If the sponsor intends to make a modification that is likely to have a substantial impact on the safety, health or rights of the trial subjects, the sponsor shall, in accordance with Section 55(1) MPDG, apply to the competent ethics committee for a statement on the notified modification via the German Medical Devices Information and Database System in accordance with Section 86 MPDG. The application must be made by submitting the updated documents referred to in Section 54(1) and stating the reasons for the modification.

Please note that all notifications may only be made in electronic form.

Exception

However, according to Section 47(3) MPDG, the above-mentioned application and notification obligations do not apply to other clinical investigation of a medical device that already bears the CE marking according to Article 20(1) of Regulation (EU) 2017/745, provided that

1. the other clinical investigation is conducted within the scope of the intended use covered by the CE marking and
2. the subjects are not undergoing any additional invasive or burdensome procedures beyond the normal conditions of use of the device.

For these clinical investigations, no application is made to the higher federal authority and the ethics committee in accordance with the MDR in conjunction with the MPDG. However, there is an obligation to obtain advice from an ethics committee in accordance with professional law (cf. § 15 Model Code of Professional Conduct for Physicians of the German Medical Association. The ethical principles for medical research involving human subjects set out in the Declaration of Helsinki of the World Medical Association also apply.

It should be noted that § 47 (3) of the MPDG only repeals the requirements of the preceding sections (1) and (2), but does not repeal legal requirements arising from other statutory provisions.

If any other clinical trial is to be conducted beyond the intended purpose covered by the CE marking and/or the additional invasive or stressful procedures are to be performed on trial subjects beyond the normal conditions of use of the device, the application and notification obligations described in the MPDG in §§ 47 ff. apply.

For the question of what is to be considered additionally invasive and/or stressful, reference is made to the recommendations of the Arbeitskreis Medizinischer Ethik-Kommissionen in der Bundesrepublik Deutschland e.V. (Working Group of Medical Ethics Committees in the Federal Republic of Germany).

Further provisions on "other clinical investigations"

With reference to the above provisions of Article 62, Article 82 establishes the following provisions for "other clinical investigations."

• Article 62 (2): Where the sponsor of a clinical investigation is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication with that legal representative shall be deemed to be a communication with the sponsor. (…)
• Article 62 (3): Clinical investigations shall be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in a clinical investigation are protected and prevail over all other interests and the clinical data generated are scientifically valid, reliable and robust.
  Clinical investigations shall be subject to scientific and ethical review. The ethical review shall be performed by an ethics committee in accordance with national law. Member States shall ensure that the procedures for review by ethics committees are compatible with the procedures set out in this Regulation for the assessment of the application for authorisation of a clinical investigation. At least one lay person shall participate in the ethical review.

• Article 62 (4): A clinical investigation as referred to in paragraph 1 may be conducted only where all of the following conditions are met:
  (…)
  b) an ethics committee, set up in accordance with national law, has not issued a negative opinion in relation to the clinical investigation, which is valid for that entire Member State under its national law;
  c) the sponsor, or its legal representative or a contact person pursuant to paragraph 2, is established in the Union;
  d) vulnerable populations and subjects are appropriately protected in accordance with Articles 64 to 68;
  (…)
  f) the subject or, where the subject is not able to give informed consent, his or her legally designated representative has given informed consent in accordance with Article 63;
  (…)
  h) the rights of the subject to physical and mental integrity, to privacy and to the protection of the data concerning him or her in accordance with Directive 95/46/EC are safeguarded;
  (…)
  

  l) the investigational device(s) in question conform(s) to the applicable general safety and performance requirements set out in Annex I 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 subjects. This includes, where appropriate, technical and biological safety testing and pre-clinical evaluation, as well as provisions in the field of occupational safety and accident prevention, taking into consideration the state of the art;

• Article 62 (6): The investigator shall be a person exercising a profession which is recognised in the Member State concerned as qualifying for the role of investigator on account of having the necessary scientific knowledge and experience in patient care. Other personnel involved in conducting a clinical investigation shall be suitably qualified, by education, training or experience in the relevant medical field and in clinical research methodology, to perform their tasks.