The regulatory review and approval process for several product categories requires the notified bodies to engage with competent authorities to seek a scientific opinion, prior to issuing an EU certificate. The consultation procedures are specified in Art. 52 and Art. 54 MDR. Depending on the device attributes, one or several procedures need to be performed by involving designated competent authorities, EMA, or expert panels of the European commission.
Many of today’s most innovative medical devices are actually drug/device products that generally combine a medical device and a drug, whereas the drug acts with ancillary function to the device. Combination products are often medical devices that have been coated or impregnated with a drug substance, such as a catheter with an antimicrobial coating, or a drug coated stent. Other examples of combination products include coated balloon catheters and bone cements containing antibiotics and condoms coated with spermicides.
According to the requirements of the Medical Device Regulation (MDR), Annex IX section 5.2, where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product, and that has an action ancillary to that of the device, TÜV SÜD will seek a scientific opinion from one of the competent authorities or the EMA prior to issuing an EU technical documentation assessment certificate.
This procedure also applies for devices which shall be certified under MDR, even if they have undergone the consultation procedure under the MDD or AIMDD already. Also, if no changes have been implemented to the medical device.
For the first consultation of legacy devices under the MDR, the notified body is required to submit manufacturer’s full documentation package to the medicinal product authority as described in dedicated guidance1 or which complies to the requirements of the competent authority. Therefore the manufacturer is required to accomplish the submission package with a consolidated list of changes, such as the following:
Where no changes to the medicinal substances are identified, TÜV SÜD will provide a declaration that no changes have been implemented since the last consultation.
For an initial consultation a medicinal authority is required to deliver the result of the assessment in 210 days2. For a consultation procedure which has already been performed under the MDD/ AIMDD and is submitted initially under the MDR, the competent authorities will consider the depth of the review given the extent of the changes since the latest valid consultation result.
The consultation procedure as described above, will also be applicable to those legacy devices, where the manufacturer had justified that the medicinal substance was not liable to act upon the body and therefore a consultation was not required to be performed under the MDD/AIMDD.
1 European Medicines Agency recommendation on the procedural aspects and dossier requirements for the consultation of the European Medicines Agency by a notified body on an ancillary medicinal substance or an ancillary human blood derivative incorporated in a medical device or active implantable medical device
2 Without clock stops in case of questions
Regulation EU 2017/745 requires notified bodies to seek an opinion from a competent authority on the quality and safety of medicinal substances incorporated in medical devices that have an action that is ancillary (i.e supports) to the action of the device. TÜV SÜD should give due consideration to the scientific opinion when taking its certification decision.
Where the device incorporates a human blood or plasma derivative or a substance that, if used separately, may be considered to be a medicinal product falling exclusively within the scope of the Annex to Regulation (EC) No 726/2004, the notified body shall seek the opinion of the EMA.
When issuing its opinion, the EMA shall take into account the manufacturing process and the data related to the usefulness of incorporation of the substance into the device as determined by TÜV SÜD.
In reviewing the data submitted by the manufacturer TÜV SÜD checks the documentation for the fulfilment of basic formal requirements as laid out in EMA/CHMP/578661/2010 rev .1. Pursuant to this guideline, TÜV SÜD has to provide a report to the EMA verifying the usefulness of the ancillary human blood derivative as part of the medical device taking into account the intended purpose of the device. TÜV SÜD will verify the usefulness of the human blood derivative acc. to the above guidelines. This verification will take in consideration the assessment of a Clinical Reviewer.
The Committee for Medicinal Products for Human Use (CHMP) can be asked to shorten the procedure in the following cases:
• the device is for use in serious diseases (life threatening or heavily disabling diseases);
• a known medicinal substance or human blood derivative from a known source is used and when CHMP considers that the evaluation needed is less extensive.
Applicants requesting an accelerated assessment procedure should provide a justification supporting their claim at least two to three months before submitting the initial consultation procedure. The application form can be found at the European Medicines Agency website.
After the evaluation period the CHMP/European Medicines Agency will issue an opinion on the quality and safety of the substance(s) including the clinical benefit/risk profile of the incorporation of the substance(s) into the medical device. The CHMP opinion is sent to TÜV SÜD and to the national Competent Authority on medical devices of the member state in which the notified body is based.
Timelines defined according to EudraLex Notice to Applicants Volume 2A, Chapter 4 are the following: Pre-submission meeting with EMA for initial certification with TÜV SÜD: 6 months before the expected submission of the documentation.
Submission of the documentation:
For devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable recently included in the MDR (Annex VIII rule 18) the following shall apply:
The classification and need of a Consultation at a European Competent Authority (CA) is verified via the application management phase. It must be clarified whether the medical device with human origin tissues or cells derivatives is covered by MDR as a medical device and a consultation according to the MDR is required.
TÜV SÜD will, prior to issuing an EU technical documentation assessment certificate, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2004/23/EC (human tissue and cells competent authority) on the aspects related to the donation, procurement and testing of tissues or cells of human origin or their derivatives which are non-viable or rendered non-viable.
The duration of the consultation procedure is 120 days and 60 days in case of changes related to donation, testing or procurement.
Such products are either biological heart valves, products made of e.g. collagen, or medical devices made from a substance of animal origin or manufactured in a process in which substances of animal origin are used.
A consultation process has to be set up for all products that include animal material derived from TSE-relevant species (e.g. bovine, ovine, caprine). To initiate the consultation, process TÜV SÜD submits the documentation pointed out in the Annex II of the Regulation 722/2012/EC to ZLG (coordinating Competent Authority) which is providing it to all Competent Authorities of the member states.
If there have been no changes to the documentation required from the manufacturer as per Regulation (EU) 722/2012 since the last consultation process, the summary evaluation report (SER) may be accompanied by a declaration by the notified body, which confirms that the elements have remained identical. If there have also been no changes to the assessment of this documentation by the notified body, this may also be included in the declaration. Should there be only administrative changes to the above (e.g. changes of names or addresses, changes in document layout, etc.), these should be clearly detailed in the declaration.
Any comments received from the coordinating and national Competent Authorities within a time frame of 12 weeks after submission of the consultation documents have to be taken into consideration by TÜV SÜD.
For devices utilising material of animal origin with a valid EDQM certificate of suitability the consultation period is reduced to 4 weeks.
As stated in Article 5(5) of Regulation (EU) 722/2012, the competent authorities and the Commission may agree on shortening the time periods for the consultation. If many elements of the summary evaluation report remain identical, it is highly recommended to expedite the review, however it has to be considered that clarification with the CA and the Commission may also take some time and the consultation timelines are anyhow restricted to 3 months.
A due justification for not taking into account one or more of the comments received from the authorities needs to be documented. A rationale for any deviation with the comment of a Competent Authority shall be documented.
A certification can be recommended after completion of the consultation period.
The results containing the summarized results of the opinion(s) of the competent authorities and the final decision of TÜV SÜD shall be notified to ZLG.
If it became evident, that the overall TSE risk in relation to the medical device has increased, a full consultation procedure according to Article 5 of Regulation 722/2012 must be performed.
The Clinical Evaluation Consultation Procedure applies to class III implantable devices and class IIb active devices intended to administer and / or remove a medicinal product (Rule 12).
The procedure does not apply in case:
The Expert Panel shall decide within 21 days whether to provide a scientific opinion. Decision criteria are as follows:
An opinion shall be delivered within a period of 60 days.
TÜV SÜD will give due considerations of the views expressed in the scientific opinion of the Expert Panel.
Where no opinion has been delivered within a period of 60 days, TÜV SÜD will proceed with the certification procedure of the device.
To be or not to be (consulted) is the question when it comes to substance-based absorbable devices.
Substances, i.e. any matter irrespective of origin (human, animal, vegetable or chemical3) have not been in the spotlight of the medical device world until the first draft of the MDR was published. Whenever peppered with “absorbable or resorbable”, they raise inquiries about the consultation. Substance-based devices that have a biological effect or are wholly or mainly absorbed4 or else intended to undergo chemical change in the body might be erroneously presumed to be consulted. But neither the vast majority of them nor their products of metabolism are necessarily systemically absorbed in order to achieve the intended purpose.
If your product falls under MDS 10085 and is systemically absorbed in order to achieve the intended purpose, it fulfils the prerequisite for the consultation of absorbable devices. TÜV SÜD stands ready to implement the specific consultation process approved by the Competent Authority. Our specialised assessors open global communications channels to compile a submission file based on the product data related to the ADME-Tox and interaction. In other words, the absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions characteristics are to be challenged against the quality and safety requirements. We seek for a scientific opinion from one of the designated medicinal products competent authorities (CA)6 or the European Medicines Agency (EMA) expected to be drawn up within 150 days of receipt of all the necessary documentation7. We give due consideration to those opinions in our final decision and notify the CA of our certification decision.
Where a substance-based device can affect the whole body, or at least multiple organ systems consultation is necessary. In contrast, if the substance-based device still falls under MDS 1008 but affects only topical or local tissues they shall not be consulted. However, we are obliged to assess the ADME-Tox and interaction survey drawn up by the manufacturer. The outcomes will be part of the final technical report and influences the EU-certification decision.
In both cases of systemically absorbable consultation or no absorbable consultation, during the initial EU certification, great emphasis is put on the overall quality and safety of the absorbable substance(s) in the MDR. The ADME-Tox and interaction data have to initially fulfil the quality and safety requirements. Also, in the event of substantial changes8, those characteristics should be maintained or not negatively impacted.
Entrust us your product portfolio and invest your time and resource in a proven capacity to combine benchmark-supported competence and flexibility that efficiently process well known absorbable devices but also purposefully plan the timing of the review towards a EU certification. Contact us as early as possible in the pre-application phase to check your decision upon the classification, and applicability of rules 8 and/or 21. As Notified Body we have to verify which MDN/MDA and MDS codes apply, and most importantly to objectively exclude or include the necessity for consultation of absorbable substance. Be a holder of EU product certificate for substance-based absorbable devices!
3 Directive 2001/83/EC, Title I Definitions, art. 1, section 3
4 MEDDEV 2.4/1 Notes 5 and 6
5 Coding for specific characteristics as per COMMISSION IMPLEMENTING REGULATION (EU) 2017/2185
6 In acc. with Directive 2001/83/EC
7 MDR Annex IX.II.5.4
8 E.g.: change in level of invasiveness; potential toxicity of products introduced into the human body; the place where the device performs its action in or on the human body or is introduced or applied; change in the absorption of the substance or the product(s) of its metabolism.