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BFARM Dialog Meeting in Bonn

Two years have passed since the introduction of the German Medical Device Law Amend-ment (21.03.2010). This was a major legal change that re-shaped the German regulatory me-dical device landscape on many levels. Before that, starting a clinical study in Germany re-quired only an Ethics Committee approval and a relatively simple local authority notification.

Since 31st March 2010, the regulatory process leading to the start of a new medical device study had to follow the new approval process, whereby BFARM played a major role. The new law, together with related ordinance (MPKPV. 13.05.2010), has defined the Ethical Commit-tee and Competent Authority approval process, and set up a new dimension of stringency on both formal and content levels. These new requirements have challenged not only medical device manufacturers and CROs, but also, the Ethics Committees and Competent Authorities themselves.

Two (2) years after the new law was implemented, BFARM took an opportunity to organize the Bonn Meeting. Its major focus was to share the related experiences of all involved stake-holders, facilitate dialog between them in order to bring more clarity, and raise issues impor-tant to stakeholders. In the end it will create solutions that will make starting of medical de-vice studies a faster and smoother process.

Detailed aspects of the approval process, challenges in differentiation between medical de-vices and other medical products, subtleties of regional and national regulations as well as various compliance topics, were presented and discussed.

One of the Bonn Meeting’s messages was that since 2011,BFARM has approved 500 studies and has granted waivers for more than 150 studies, emphasizing that that despite of the new regulatory challenges, Germany is still the number one choice for performing medical device studies. This was additionally confirmed by the EU wide statistics presented, where Germany was the most popular choice for Medical Device clinical studies. As many as 28% of studies were organized with participation of German investigational sites, a result that leaves any other EU country far behind.

One of the key take home messages that we would like to quote here – were the most com-monly encountered formal deficiencies in the applications for BfArM approval.

They are:

• Required documents are not submitted or there is no cross-reference available
• The table of contents is not clear
• Documents are difficult to be found (large document sets poorly organized)
• Documents are simply missing
• Authorization is missing (e.g. necessary signature pages are not provided)
• Pre-clinical or technical testing is not finalized prior to submission
• Process for SAE notification is not according to current guidelines (BfArM or MPSV guidelines)

The guidelines on how to avoid these deficiencies were also provided. They are as follows:

• To Know the European and German regulations, in particular of MPKPV and MPSV
• To provide documents and cross-reference table for all required items
• To provide a cover letter summarizing the most-important aspects of the clinical trial
• To have all the required documents in place at the application time – to submit them ini-tially or eventually have them ready in case of enquiry
• All documents should be legible, understandable, and well organized

Next, we draw your attention to additional useful information from this meeting and from the recently published article "Approval process of clinical studies with medical devices" (Fischer et al. Bundesgesundheitsbl. 2012, 55:270-276). We already shared with you the typical shortcomings on the formal level encountered in the BFARM applications for approval and the ways to prevent them. Now we will quote BFARM`s experience on their most frequently observed shortcomings in medical device study applications as far as the content is concerned.

These shortcomings are as follows:

• The Clinical Investigational Plan (CIP) is not consistent with current state of the scientific knowledge and Good Clinical Practice (GCP)
• The risks associated with the clinical trial and the medical device are not at all or insufficiently presented and confronted with the benefits
• Alternative treatment options were not taken into account
• The biological safety testing is not complete
• The proof of safety-related harmlessness is missing
• Documentation does not correspond to the current state of the art
• A validated sterilization procedure is not in place

BFARM suggests how to prevent these shortcomings:

• To assure that clinical trial follows the principles of Good Clinical Practice (GCP)
• To assure that the risks and benefits associated with the clinical trial are adequately assessed
• To take into account the current state of the scientific knowledge including the medical standards
• To finalize all required pre-clinical and technical testing
• To take into account the current state of art including the current standards
• Rationale is to be given in case of deviations from current state of the science or state of the art
• The technical documentation needs to be presented and organized in an easy to follow and clear fashion

In case of certain low risks medical device trials (for more information please see Section 20 of the German Act on Medical Devices) BFARM can waive the authorization. Applications for such waivers although very much simplified as compared to the standard authorization process still pose certain difficulties to the applicants. Therefore, a short summary of waiving applications shortcomings was presented as well.

These shortcomings are:

• Device Classification is incomprehensible
• Declaration of conformity is not valid
• The description of the intended use is unclear
• The risk-benefit summary does not include all risks
• Validated sterilization procedure is missing (for sterile, non CE-marked products)

As previously it is advised how to avoid these shortcomings:

• Classification needs to follow Appendix IX of directive 93/42/EEC
• Declaration of conformity shall follow the amending directive 2007/47/EC
• The use of the medical device within the clinical trial according to its intended use and the current medical standards is clearly presented
• All Risks are summarized and evaluated
• If applicable, certification for valid sterilization is attached

Finally in both the above mentioned article as well as during the meeting, BFARM emphasized its efforts to conduct the application review process in a cooperative and partnership based fashion. It was also made clear that BFARM personnel are easily available by phone and email for specific questions and advice. Our CRO experiences confirm that and we highly recommend searching for specific assistance before and after the application has been done.

By doing so, the applicants assure maximum compliance with BFARM requirements. Moreover, BFARM can offer scientific advice services focusing on specific issues related to device development processes as well as the clinical trial design well before the application for authorization is complete. This is especially recommended in case of combination products (device with medicinal product) and highly innovative medical devices.