An increasing number of medical devices requires a consultation process under the new EU-MDR. More specifically, the conformity assessment procedure of the medical device requires the Notified Body to contact a national competent authority, for their review and feedback. Only then, an EU technical documentation assessment certificate can be issued for the device. Has anything changed in the consultation process under the new Medical Device Regulation (MDR)? The answer is yes.
Devices which incorporate, as an integral part, ancillary medicinal products (regular combination products)
In essence, the consultation process for combination products, as class III medical devices, has not changed dramatically under the new MDR. For combination products, a consultation process is required either with a European Medicinal Component Authority (CA) or with the European Medicines Agency (EMA). The consultation process will include aspects on quality and safety of the drug substance alone, and also the usefulness of incorporation of the drug into the device.
Steps in the consultation process include: (i) consultation request by the Notified Body (NB) to the relevant CA/EMA, (ii) pre submission procedure, usually including also a meeting to be attended by the NB and the manufacturer, and (iii) the final submission of the dossier for review. The CA/EMA will provide an assessment report at the end of the review process, within 120 days, with their overall opinion on the quality and safety of the drug substance. In contrast to the MDD, under the MDR the NB shall not deliver the certificate if the scientific opinion is unfavorable.
One thing that is unclear at this stage is whether the existing reviews may form the basis of certification under MDR, or if a top up is needed. Secondly, with the details of the post-Brexit status of MHRA still to be clarified, the historic 30% of consultations done by them are potentially at risk of having to be repeated.
It is interesting to note that in rule 14, which is applicable for combination products, the wording “liable to act on the human body” was purposefully removed from the MDR. That means that a device that incorporates even only some molecules of a medicinal substance will always fall under rule 14 regardless of the concentration of this substance Hence many devices that previously found an ‘escape route’, now will be classified as combination products. It is expected that for many of them the investment in the new process will not be taken by the manufacturers.
Devices utilizing biological tissue (human/animal) or derivatives
The scrutiny of the authorities over medical devices manufactured utilizing tissues of animal origin started after the BSE (Bovine spongiform encephalopathy) crisis in the late 1980’s and early 1990’s, which in its latest revision led to the legislation of EU Regulation 722/2012. The consultation process is required for devices which fall under rule 18 of the MDR and for which EU Regulation 722/2012 applies. This Regulation is however only applicable to tissues originating from TSE-susceptible species (e.g. bovine, ovine, caprine, deer, elk, mink, cats).
For animal tissue, the steps of the consultation process are already described in EU Regulation 722/2012. Therefore, no change has occurred under the new MDR, other than the fact that EU Regulation 722/2012 is now specifically mentioned in the text. NB's should assess the documentation submitted by the manufacturer to verify that the benefits of the device outweigh the residual risks. The documentation includes: (i) risk assessment following EN ISO 22442-1, (ii) justification for the use of animal tissues or derivatives, taking into consideration lower risk tissues or synthetic alternatives, (iii) results of elimination and inactivation studies or results of the analysis of relevant literature, and (iv) manufacturer’s control of the sources of raw materials, finished products, production process, testing, and subcontractors.
The NB must review and prepare a Summary Evaluation Report (SER), submitted to the coordinating CA, which then informs the CAs of other member states and the Commission. The NB has to review all the comments made by the CAs and to give ‘due consideration’ before issuing a certificate.
However, rule 18 of the MDR now includes the addition of tissue or cells of human origin, which is a new addition to the scope compared to rule 17 of the MDD. It is important to note that “utilizing” in this context implies that the biological tissue does not necessarily have to be incorporated in the final device, it can be part of the manufacturing process only. Therefore, a consultation process is also applicable for devices manufactured by utilizing derivatives of human tissues or cells and for devices that incorporate, as an integral part, human tissues or cells, or their derivatives, that have an action ancillary to that of the device.
The consultation process requires that the NB seek a scientific opinion from one of the ‘human tissues and cells competent authorities’ on the aspects relating to quality and safety for the donation, procurement and testing of tissues or cells of human origin or their derivatives. The risk or benefit of the incorporation of the human tissues or derivatives into the device should also be included in the summary report submitted by the NB to the relevant authority. Same as for combination products, the NB shall not deliver the certificate if the scientific opinion is unfavorable.
As this is a new process, the first couple of procedures are expected to find delays and need for debates on the implementation of the new MDR expectations.
Devices which are absorbed by or locally dispersed in the human body
The EU-MDR introduces a new rule, Rule 21, which covers devices that are composed of substances (or combination) that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body. These kinds of devices can be classified as IIa, IIb or III, depending on their mode of action.
A consultation process is also required here to put the product on the market. The NB should seek a scientific opinion from one of the medicinal products CA or EMA on the compliance of the device with the relevant requirements laid down in Annex I to Directive 2001/83/EC. Examples of topics to be evaluated are absorption, distribution, metabolism, excretion, local tolerance, toxicity and interaction with other devices, medicinal products or other substances and the potential for adverse reactions. The NB has to give ‘due consideration’ to the scientific opinion before issuing a certificate and to inform its final decision to the medicinal products authority consulted. As for most such products, these data are unavailable at this stage, and return on investment for quite some products will not be feasible, this new requirement will have a distinct effect on availability to the market of the covered devices.
To conclude, devices which require consultation process were already classified under the MDD as high-risk devices and therefore the authorities apply a higher level of scrutiny on them. Thus, it is not surprising that there are no substantial changes with respect to the conformity assessment routes to be followed under the MDR. Nevertheless, manufacturers should understand what is required of them, and the subtle modifications within the MDR, in order to be in compliance with the regulatory requirements. Early planning of your submission process could save a lot of time and resources in later stages.
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