Information on submission of a request for authorisation of a clinical trial or a performance evaluation study
Information on submission of a request for authorisation of a clinical trial or a performance evaluation study to the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) in accordance with Section 22a of the German Act on Medical Devices
In accordance with Section 20 sub-section 1 of the German Act on Medical Devices ("Medizinproduktegesetz", MPG) as amended on 21 March 2010 (cf. Article 6 of the Law of 29 July 2009 (Bundesgesetzblatt [Federal Law Gazette] BGBl. I page 2326)), conducting clinical trials of medical devices and performance evaluation studies of In-vitro Diagnostic Devices (IVDD) requires authorisation by the competent federal higher authority ("Bundesoberbehörde").
In order to initiate the authorisation procedure for clinical trials of medical devices and performance evaluation studies of IVDD a request is to be submitted to the competent federal higher authority. This publication gives further information on the documents to be submitted in accordance with Section 3 of the Ordinance on Clinical Trials with Medical Devices ("Verordnung über klinische Prüfungen von Medizinprodukten", MPKPV). These statements are based on the statutory provisions valid as of 21 March 2010 as well as on normative regulations and European Directives. This publication is supposed to enable correct submission of the request thus promoting an effective authorisation procedure.
The following information does not affect the applicant's obligation to submit further documents not listed here in the course of an application for a favourable assessment from the Ethics Committee.
The requirements to be met by the sponsor as well as the scope of the federal higher authority's evaluatory tasks within the authorisation procedure are described in Section 22a sub-sections 1 and 2 MPG.
Authorisation by the federal higher authority
(1) The sponsor must apply for the authorisation required in accordance with Section 20 sub-section 1 sentence 1 with the competent federal higher authority. With the exception of the opinion of the Ethics Committee concerned, the request must contain information as specified in number 2.2 of Annex 6 to Directive 90/385/EEC in the case of active implantable medical devices and as specified in number 2.2 of Annex VIII to Directive 93/42/EEC in the case of other medical devices. Additionally, the sponsor shall submit all information and documentation required by the competent federal higher authority for evaluation. The assessment of the Ethics Committee is to be supplemented. Details on the procedure are specified in a statutory regulation pursuant to Section 37 sub-section 2a.
(2) The competent federal higher authority has the task of evaluating the protocol and the necessary documents, especially under scientific and technical aspects, with regard to whether the prerequisites in accordance with Section 20 sub-section 1 sentence 4 numbers 1, 5, 6 and 8 are fulfilled.“ [Unofficial translation]
The application in accordance with Section 22 sub-section 1 sentence 1 and Section 22a sub-section 1 sentence 1 MPG is to be submitted by data transmission via the central data collection system of the German Institute of Medical Documentation and Information [Deutsches Institut für Medizinische Dokumentation und Information, DIMDI]. The DIMDI's application form requests all information necessary for processing.
In addition to the information listed in the DIMDI's template, the application is to be accompanied by the following documents, in German or English as applicable in the individual case, unless expressly specified in the following that submission is to be in German (Section 3 MPKPV):
- The trial protocol - or, in case of a performance evaluation study, the evaluation protocol - signed by investigator, leading investigator of the clinical trial or the performance evaluation study as well as by the sponsor or appointed representative,
- the investigator's brochure,
- a summary of the main content of the protocol - or, in case of a performance evaluation study, the evaluation protocol - in German if originally written in English,
- the description of the intended medical procedure and examination methods as well as possible deviations from medical standards,
- the preclinical assessment,
- information on safe use of the medical device in German,
- an evaluation and assessment of the foreseeable risks, disadvantages and stress for the trial subject weighed against the prospective significance of the medical device for medical science and against the anticipated benefit for the trial subjects,
- an assurance that the medical device concerned fulfills the essential requirements in accordance with Section 7 MPG with the exception of the issues that are the objective of the trial and that all precautionary measures for the health protection and safety of the trial subjects, the users, as well as third parties have been taken with regard to these issues,
- a protocol for follow-up treatment and medical support of trial subjects,
- reasoned negative opinions from the competent Ethics Committees of other Member States of the European Union or other contracting parties to the Agreement on the European Economic Area as well as refusals by the competent authorities of other Member States of the European Union or other contracting parties to the Agreement on the European Economic Area,
- a power of attorney for the representative appointed by the sponsor according to Section 20 sub-section 1 sentence 4 number 1a MPG,
- the results of biological safety testing or other tests required for the intended use of the medical device in accordance with Section 20 sub-section 1 sentence 4 number 5 MPG,
- proof of technical safety in accordance with Section 20 sub-section 1 sentence 4 number 6 MPG,
- the descriptions and instructions necessary for understanding the function of the medical device,
- the risk analysis and assessment including description of the known residual risks,
- a list showing adherence to the essential requirements of the pertinent regulations including statement of the standards and common technical specifications employed entirely or partially as well as a description of the solutions for adhering to the essential requirements in case these standards were not adhered to or are missing,
- in the case of reusable products or products to be sterilised prior to use, proof of validation of the manufacturer's sterilisation procedures or statements regarding the reprocessing or sterilisation procedures to be performed by the trial site,
- descriptions of the procedures for documentation, evaluation, and reporting of serious adverse events (SAEs) to the competent federal higher authority.
In as far as documents are part of the protocol or investigator's brochure cross-referencing is sufficient.
The trial protocol should include the particularities of the trial, e. g. if the trial includes subjects requiring special protection, such as minors, adults that cannot give their informed consent, or pregnant or lactating women, or if it is performed concurrently with another clinical trial within a different legal frame, as in the case of studies including a medical device and a medicinal product in one trial. It is pointed out that additional requests for authorisation may become necessary depending on the relevant regulations of the Medicines Act, the X-Ray Ordinance, or the Radiological Protection Ordinance. A detailed discussion of the statistical interpretation and significance that are object of the study design is necessary.
Assessment and justification of the risks for the individual trial subject participating in the clinical trial, weighed against the prospective significance of the medical device for medical science, should be presented. Alternative possibilities for gaining scientific knowledge, lower-risk alternatives, as well as the current state of medical science used as comparison should be described in detail.
The follow-up care procedure must also assure proper medical treatment and support of the trial subjects in case of suspension or premature termination of the trial. This is especially important in trials involving implants. The follow-up procedure for trial subjects may necessitate immediate unblinding and decoding of part of the trial population. In such cases the possibility of continuing the trial for those parts of the trial affected or not affected by the corrective measure needs to be considered.
The procedure for reporting and autonomous investigation of SAEs has to describe and ensure the implementation of regulatory provisions both on the European and national level (cf. German Ordinance on Medical Devices Vigilance, "Medizinprodukte-Sicherheitsplanverordnung"). It is to be assured that the sponsor makes use of the reporting form for SAEs published by BfArM. The reporting system must allow a definite attribution of SAEs report to trial and trial site. This is achieved by coding according to the following pattern: Code1/Code2/Code3.
Code 1 stands for the clearly allocated identification number of the trial (study code), Code 2 stands for the unequivocal code of the trial site assigned by the sponsor and Code 3 is the consecutive numbering of the reports.
Risk analysis and assessment should reflect the procedures of the pertinent harmonised standard and are to be updated regularly in the course of the clinical trial. This is especially important when evaluating SAEs and the implementation of corrective measures in accordance with the Ordinance on Medical Devices Vigilance.
Within 10 days, the BfArM will send the applicant a confirmation of receipt of the application in due form stating the date of receipt. The time frame of 30 days referred to in Section 22a sub-section 4 sentence 1 MPG does not start until all documents necessary for the application have been received (Section 6 sub-section 1 MPKPV).
The authorisation shall be deemed granted if the competent higher federal authority fails to communicate to the sponsor any objections together with the grounds therefor, within 30 days subsequent to the submission of the application documents. If the sponsor fails to modify the application to meet the reasoned objections within a deadline of 90 days, the application shall be deemed refused. Please note that this deadline refers to calendar days and can not be extended.
Prior to submission, applicants have the possibility of contacting the BfArM at the e-mail address firstname.lastname@example.org and receiving scientific advice from the BfArM. Before seeking such scientific advice please observe the corresponding information on the BfArM's homepage.