MDR 2017/745 Art. 82 Other Clinical investigation with Medical Devices: submissions in Germany

Introduction

The principle of ISO 14155:2020 Annex I post-market stage applies to clinical investigations as per MDR 2017/745 Article 74.1 PMCF clinical investigations and the Art. 82 other clinical investigations.

This blog refers to the current submission requirements for an MDR 2017/745 Art. 82 Other Clinical Investigation in Germany.

When is the Clinical Investigation an Art. 82 Other Clinical Investigation?

As set out in MDR 2017/745 and MDCG 2021-6 it is an Article 82 other clinical investigation, if:

• It is an interventional clinical investigation with a CE-marked or non-CE marked device, but not for purposes of Art. 62.1 (example: CE marked Stent, investigation to explore the impact on blood flow; non-CE marked smart monitoring device, investigation to explore changes in the behavior of subjects when using the device)
• clinical investigations with CE-marked devices, within the scope of intended use and without any additional burden to the subject fall under the post-market stage (observational)

• clinical investigations with CE-marked devices, within the scope of intended use, without any additional burden to the subject, but not for safety and performance would be post-market stage (observational), but are out of scope of the MDR 2017/745.
  

However, this does not imply that they are out of scope of the national regulations of a Member State as well.

Other clinical investigations need to comply with Article 62(2) and (3), (4)(b), (c), (d), (f), (h) and (l), and (6):

• Protection of the rights, safety, dignity and well-being of the test subjects; scientific and ethical test
• investigational device complies with the essential safety and performance requirements set out in Annex I, with the exception of the items that are the subject of the investigation
• consent of the subjects, proof of qualification of the investigator
• Protection of privacy and personal data

How is the Art. 82 Other Clinical Investigation regulated in Germany?

The Medical Device Law Implementation Act (Medizinprodukterecht-Durchführungsgesetz, MPDG) provides the definition, and thus the base for the national regulation of this kind of studies in § 3 (4):

“§ 3 (4) ‘other clinical investigation’ of a device means a clinical investigation that

1. is not part of a systematic and planned product development process or the product monitoring process of a current or future manufacturer,
2. is not conducted with the objective of demonstrating the conformity of a device with the requirements of Regulation (EU) 2017/745,
3. serves to answer scientific or other questions; and
4. outside a clinical development plan according to Annex XIV, Part A, point 1(a) of the Regulation (EU) 2017/745 “

While MPDG § 47 lists the requirements for “other clinical investigations”, § 47 (3) clarifies, which Other Clinical Investigations do not fall in the scope of the MPDG, and it is as it was before MDR 2017/745 and MPDG became effective:

Ҥ 47 (3) Paragraphs (1)[requirements for conduct of CI] and (2) [requirements for start of CI] shall not apply to any other clinical investigation of a device which already bears the CE marking in accordance with Article 20(1) of Regulation (EU) 2017/745, provided that

1. the other clinical investigation is carried out within the scope of the intended purpose covered by the CE marking and is conducted, and
2. the subjects of the investigation are not subjected to any invasive or stressful procedures beyond the normal are subjected to.”

For these clinical investigations the EC consultation as per § 15 BOÄ (Berufsordnung der Ärzte, Professional Code of Physicians) applies.

CA Notification requiring Other Clinical Investigations

For this kind of clinical investigations, the submission process now needs to be done via BfArM’s (Bundesamt für Arzneimittel und Medizinprodukte, Federal Office for Pharmaceuticals and Medical Devices) DMIDS (Medizinprodukte-Informations- und Datenbanksystem, German Medical Devices Information and Database System).

It is a sequential submission process, the submission package for the initial submission needs to include all required documents.

The EC’s do not need to provide a written favorable opinion. The favorable opinion will be considered implicit if no negative opinion of the EC was provided at the end of the ECs review timeline. For the notification to the CA, only the Clinical investigation Identification Number (CIV-ID) needs to be provided for the notification to the CA. The clinical investigation can commence after no objection of the EC was received, and the CI was notified to the CA.

Submission Documents

Documents required to support a submission with respect to Annex XV, Chapter II MDR 2017/745 are listed below.

• Cover letter
• Billing address
• Clinical Investigation Plan (CIP)
• Investigator’s Brochure
• Synopsis of the CIP in German
• Description of procedure/investigational methods
• Preclinical evaluation
• Instructions for use in German
• Risk Assessment
• Assurance General Safety and Performance Requirements
• Plan for further treatment of subjects
• Power of attorney for representatives
• Results of biological safety assessment
• Proof of technical safety
• Functionality of Medical Device (MD)/information on MD
• Risk analysis and assessment including residual risks
• List of essential safety and performance requirements
• Safety reporting Declaration
• Information Investigational Site Feasibility
• Qualification of other personnel
• Qualification investigator
• Subject/patient information, declaration of consent
• Justification inclusion of particularly vulnerable persons
• Evidence of insurance
• Declaration of inclusion of dependent persons
• Declaration of data protection
• Financing of the Clinical Investigation/essential contractual contents
• Criteria or conditions and procedures for suspension or termination
• Summary risk assessment
• Evidence/data for sterile applied MP or sterilization validations
• CV of Investigator
• Proof of experience in the field of application of MD
• Proof of familiarity with basic principles of MD law
• Proof of familiarity with legal/scientific basics of the Clinical Investigation
• Demonstrated familiarity with CIP / IB
• Evidence of CE marking, if applicable
• Information on the drug, tissue, or derivative
• Technical documentation
• Optional attachments

• The PDF form of the application, including the list of attachments, is automatically generated by the system

• The Clinical Investigation Identification number (CIV-ID) will be provided by the DMIDS.
  
  
  

Submission Timelines

EC:

• 10 days for validation of the submission
• Date of confirming completeness is the validation date
• If the submission package is incomplete, the Sponsor has 10 days to complete the application
• Lead EC: 30 days for review after Validation Date, additional 7 days if an expert is to be involved
• Local EC: 20 days for review after Validation Date
• The EC may request additional information once during this time.
• Sponsor needs to provide the requested information within 45 days
• The EC will provide an opinion, either positive or negative for the CI

The reviewer clock-stops when additional documents are requested.

The timeline for the EC review can be calculates as follows:

1. If the submission package is complete from the beginning, no formal requests = 30 days for EC review (+ 7days if an expert is involved and clock-stop time to be considered)
2. If the submission package is formally incomplete and EC sends a request within the time for validation= 40 days for EC review (+ 7days if an expert is involved and clock-stop time to be considered)

CA:

• Not applicable, as no verification of the submitted documents by the CA.
  
  

Other Clinical Investigations falling in the Scope of MPDG § 47 (3) and § 15 (Berufsordnung der Ärzte, Professional Code of Physicians)

The procedure of a submission is based on a different legal basis. As we have the EC submission initiated by the Sponsor for positive opinion for a clinical investigation (MDR Articles 62, 74 (1), 74 (2), and 82/MPDG §3 47-53), a clinical investigation per § 15 BOÄ is submitted by the Principal Investigator (PI), as it is his obligation to confirm a consultation is carried out which aims at the professional ethical and legal issues related to it, prior to the implementation of the research project.

Where the Clinical Investigation falls into the scope of MPDG § 74 (3) and BOÄ § 15, documents, timelines, submissions, etc. are not regulated by law. There is only a submission to the EC to be performed, and a positive opinion from the EC required to commence with the Study. The CA is not involved.

For required documents, a check of the web site of the participating ECs is strongly recommended, to meet requirements and expectations, see information of dates and conditions of EC sessions, and modalities of submission routes.

Documents for submission include, but are not limited to:

• Cover letter
• Special Power of Attorney, if a CRO or the sponsor submits to the EC on the PI’s behalf
• Clinical Investigation Plan (CIP)
• CIP synopsis
• Patient information incl. consent form paginated with version number (in case of minors capable of consent, additionally an appropriate child-friendly information/ consent form) in its final form
• Patient information for research project not covered by AMG/MPG.
• Information on funding
• Information on registration in a publicly accessible database
• Copy of insurance policy or justification why insurance is not necessary
• Curriculum vitae of the principal investigator and participating physicians
• Questionnaires
• CRF
• Statement of the responsible data protection officer (DPO)
• Statement that the principles of the current version of the Declaration of Helsinki have been taken into account.
  
  

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