Regulation on medical devices 2017/745 (MDR): focus on substance based medical devices
The opportunity to focus attention on the topic of the future that awaits medical devices based on substances (for simplicity, SMD), as consequence of the entry into application of the new European Regulation 2017/745 on medical devices (set for May 2020), starts already with Preamble (59), that underlines the lack of sufficient prescriptions in the matter of invasiveness and potential toxicity of SMD in the context of the current regulatory framework (European Directive 93/42/EEC), as well as the lack of classifications that reflect their risk levels. Thus, it was right away imaginable that MDR would have tackled some aspects with more details and it would have provided for an increase of the risk classes related to SMD.
Another reason to focus on SMD is due to the evident distance between the consistent quantity of products on the market today with respect to the actual indifference of the old regulatory framework to said category, to the point that it can be roughly stated that SMD were not subject to interest and consideration in the current old directive, except for SMD containing a substance that taken alone can be considered as a medicinal substance or blood derivative. Two consequences descended from the situation that unfolded through the years: the actual difficulty to legally framework and to manage a SMD in conformity to the directive and the spread of products too borderline among different regulatory frameworks (medical devices, medicinal substances, cosmetics, biocides, etc.), it is sufficient to recall the borderline manual updated several times by the stakeholders chaired by the European Commission.
It was predictable that the legislator direction would have been to reverse the course and to put particular attention on SMD in the new MDR. The first change is surely to have attributed a more effective and clear meaning to the statement “assessed and authorised” already present in Art.1(4) of the old MDD and proposed again in Art.1(8) of the new MDR, with respect to medical devices containing ancillary medicinal substances or human blood derivatives. In fact, at variance with the current situation where the opinion of the consulted Competent Authority is binding only for blood derivatives (v. point 7.4, Annex I versus point 4.3, Annex II or point 5, Annex III), the new MDR establishes that the Competent Authority opinion is binding for medical devices containing an ancillary medicinal substance too (v. point 5.2, letter e, Annex IX). Thus, at least for the aspect pertaining the binding opinion on some medical devices, the concept of authorisation could find its reasoning, given that it is properly used only within the framework of medicinal substances according to Directive 2001/83/EC (Marketing Authorisation), but not for medical devices. At last, it has must be noticed that the authorisation is a requirement never referred to in the process of placing on the market of any medical device, except for the reprocessing (Art.17) and in case of public interest or patient safety and health concern (Art.59).
Going back to SMD, the most evident change is the identification of a specific group of SMD subjected to particular scrutiny through special conformity assessment procedures, as provided for in Art.52(11): devices that are composed of substances or of combinations of substances 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. This category could not embed all of SMD, but I think it comes pretty close to it. How many SMD would be kept out? What could be the fate of a substance that is not absorbed nor dispersed?
Rule 21
For said SMD category the new Rule 21 has been introduced (point 7.8, Annex VIII) that establishes class IIb as the default risk class the, rising to class III for those SMD intended for the stomach or lower gastrointestinal tract and that are systematically absorbed by the human body, as well as those SMD systemically absorbed by the human body in order to achieve the intended purpose, ultimately leaving class IIa to those SMD which are applied to the skin or in the nasal or oral cavity as far as the pharynx, and achieve their intended purpose on those cavities. No more class I for those SMD called out by Rule 21, which is not present in the current old directive. For said SMD the most evident and burdensome obligation is given by point 5.4, letter a, Annex IX. It requires the verification of the quality and safety of the product in conformity to applicable prescriptions in Annex I to Directive 2001/83/EC on medicinal substances, for the assessment of: absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances, and potential for adverse reactions. In practice, it is looming a situation in which evidences will be required in accordance to Module 4 on pharmacokinetics (point 4.2.2) and to Module 5 on reports of human pharmacokinetics studies (point 5.2.3) for absorption, distribution, metabolism, and excretion. Plus, evidences of type required by Module 4 on toxicology (point 4.2) for the local tolerance and toxicity.
For the subgroup of products given by those devices, or their products of metabolism, that are systemically absorbed by the human body in order to achieve their intended purpose, a process of consultation is provided for that includes seeking a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA (point 5.4, letter b, Annex IX), although not binding (according to letter d) for the Notified Body involved in the certification of the device.
At the same time, the subgroup given by those devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed in the human body is subjected to point 12.2 of Annex I (thus a General Safety and Performance Requirement that as such is always applicable to the said subgroup), whose requirements follow the same given above in point 5.4(a) of Annex IX. Likewise, the said subgroup is subject to prescriptions of point 6.2(c) of Annex II on the aspects covering the verification and validation of the product inside the Technical Documentation.
This summarised overview is related to a set possibly smaller than the whole quantity of SMD. It is predictable that requirements enforced by MDR to this subset of SMD will make their management much more burdensome for the manufacturer, in terms of resources, time, and professionals needed. It is also predictable that a way to avoid the issue deals with the denial that your own SMD is absorbed or locally dispersed in the human body. This hypothesis would open up the possibility to make the SMD fall in class I, for which certification by a Notified Body will not be necessary. You would argue whether in such hypothesis the MDR will be anyway able to put in place other means to oversee effectively the correct application of the Regulation itself (through the examination of the information provided to the centralized databank or Eudamed?!).
At last, as outlined at the beginning, SMD can quite frequently fall in the borderline zone among several legal frameworks. This issue is addressed by MDR in Preamble (7) to (9) already, but anyway leaving to the Member State the authority to decide on a case by case approach the legal status of a product, in accordance with the jurisprudential tradition established in the Union (v., sentence HLH Warenvertriebs et Orthica, cit. point 56). In any case, Art.4 introduces the possibility that Implementing Acts, established with the previous support of MDCG, could determine the legal status of given products, categories, or groups of products as medical devices.
