EU regulators grossly misrepresent non-invasive brain stimulation

The regulation of neuromodulation in the EU has been a muddy topic for years, and regulators recently made it all much more difficult. A new misguided reclassification rules that although some neuromodulation “equipment is not surgically invasive”, its effects do “penetrate the cranium” and must thus be regulated in Class III as other surgically invasive technologies. This puts non-invasive brain stimulation in the same class as e.g. a pacemaker, and this interpretation is expected to be picked up by other regulatory authorities who are yet to clearly regulate these technologies. The result is limited patient and researcher access to these safe and effective treatments, thus as a community we must request that the reclassification is revised to be aligned with the available scientific evidence.

In the reclassification, the EU targets Equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain (via Section 6 of Annex XVI to Regulation (EU) 2017/745) – I will refer to this as non-invasive neurostimulation (NIBS).

It is important to emphasize that the EU has, so far, only reclassified “devices without an intended medical purpose”. But their description of NIBS is portraying the technologies generally but incorrectly, and in a way that does not distinguish between medical and non-medical use:

According to available scientific evidence on equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain as referred to in Section 6 of Annex XVI to Regulation (EU) 2017/745, such as those for transcranial magnetic stimulation or transcranial electric stimulation, the use of such products may cause side effects, for example, atypical brain development, abnormal patterns of brain activity, increase metabolic consumption, fatigue, anxiety, irritability, headaches, muscle twitches, tics, seizures, vertigo and skin irritation at the electrode site. While such equipment is not surgically invasive, the electrical currents or magnetic or electromagnetic fields do penetrate the cranium to modify neuronal activity in the brain. Such modifications can have long-lasting effects and any unintended effects may be difficult to reverse. Such products should therefore be classified as Class III. (Section 7 of (EU) 2022/2347)

This is essentially a generic, but scientifically unfounded, description of the nature of NIBS technologies, and does not clearly address why this would be any different for medical use. Numerous countries around the world either follow or directly adopt EU regulations, so the new reclassification might lead to unreasonably restrictive regulation of neuromodulation globally. Thus the result will be less access for patients, clinicians and researchers, which might in the end have negative impacts for mental health globally. Ironically, the EU is currently hearing a document about “a comprehensive approach to mental health” initiative, where accurately regulated NIBS could have played an important role.

It is our duty to challenge this reclassification, to ensure that as a minimum:

1. The reclassification is informed by the best available scientific evidence.
2. All interested parties, be they experts or individuals or groups affected, have expressed their views and provided relevant data.
Both are core principles in EU’s internal Better Regulation guidelines.

Neither of these have been done in the newly adopted reclassification, and this leads to significant errors in the document, which need to be addressed and revised.

We, as a community, have to come together in a joint effort to push back. Some examples are the manifesto recently published by The European Society for Brain Stimulation (ESBS), the ongoing mapping of the state of regulation of TMS and TES around the world (participate here), and the LOTES-2017 document (and the in-press 2023 update). But much more can, and must, be done.

Background

- In the past, the EU has not specifically regulated NIBS (under the old MDD regulatory framework), but depending on its use NIBS could be consumer technology (regular CE), or medical Class I (low risk, non treatment), Class IIa (manageable risks, approved treatment effects).
- In May 2021 the new MDR was introduced to replace the MDD. Under the MDR, NIBS for non-medical use is specifically mentioned (which is quite unusual) in Annex XVI, which also includes five other product categories including contact lenses and tattoo/hair removal equipment.
- Most devices with a valid certificate under the MDD, including NIBS Class I and Class IIa products, can remain on the market in accordance with MDR Article 120 transitional provisions, until May 2024 at the latest.
- Sidenote: Due to a critical lack of Notified Bodies (NB), the organizations who are approving medical products on behalf of the EU, it is becoming clear that the transition deadline in May 2024 is no longer realistic. The EU has recently finished a public hearing for a proposal to extend the transition period, and the statistics they present there – outlining the critical lack of NB’s – is indeed worrying.
- From the initial publication of the MDR it was widely accepted that according to the MDR classification rules both medical and non-medical use of NIBS would be regulated as Class IIa. The requirement for both medical and non-medical use, as all other medical devices, is to clearly mitigate any risks to achieve an acceptable risk/benefit balance, through a data-based ‘clinical evaluation report’.
- In a letter of 28 July 2022 “certain Member States jointly requested the reclassification of several active products without an intended medical purpose” (Section 2 of (EU) 2022/2347) from Annex XVI – these include NIBS. I have requested this letter from the EU, but so far they have not been able to produce it.
- After a worryingly short process, two weeks later the EU Medical Device Group (SANTE.D.3) had a draft reclassification ready (August 11th). This draft was published for the normal 8 week hearing period on the Have Your Say platform, but due to reasons unknown to me (probably as it was classified differently) neither I nor anyone else seems to have been notified about this through various regulatory monitoring services. Thus, the draft only received 21 comments, in contrast a closely related document for Annex XVI had 2225 registered feedbacks in the same hearing period.
- In the reclassification, there is a brief and flawed description of the risks associated with NIBS (see above), and a conclusion that because of these risks NIBS for non-medical use has to be regulated as Class III.
- On December 1st the final version of the reclassification was published, and in effect from December 22 adopted.
- To the best of my knowledge, the adoption was not approved by the EU parliament, so this is an example of bureaucrats acting on their own initiative without political oversight. Only the Medical Device Coordination Group (MDCG), which consists of bureaucrats from the medical authorities in EU member states, was consulted.
- In December I requested the documentation and references behind “According to available scientific evidence” (Section 7 of (EU) 2022/2347) from SANTE.D.3. They were not able to provide me with this within the legal 15 working day deadline for such requests, and have now, “in line with Article 7(3) of Regulation (EC) No 1049/2001”, granted themselves another 15 working days to provide the evidence. It is worth noting that for SANTE to write the reclassification took two weeks, but providing the evidence used will take six weeks.
- The two direct implications of the reclassification are: a) Any NIBS legacy products from the MDD without an intended medical purpose will have to comply with Class III transition clauses during the transition process. And b) any new non-medical NIBS product in the EU will, effective December 22nd 2022, have to comply with Class III rules – the same rules applied to surgically invasive equipment.
- The impact the document will have on the regulation of medical NIBS devices is unknown.

Why is this a problem?

While we all support sound and science based regulation of technology, and potentially some NIBS technologies do in fact belong in Class III, there are some major challenges with the newly adopted reclassification. These flaws will potentially limit the access to these technologies in treatment for patients and clinicians, first in the EU but likely other areas later as many other countries either adopt MDR directly or follow it closely.

The main problems with the reclassification are:

1. The exact wording in the reclassification is a description of the inherent risk in NIBS technologies, unrelated to how they are being used. So while the text is in the context of non-medical use, the document effectively classifies all NIBS as Class III risk. If the document explained how the listed risks are only present in non-medical use, it would be less of a problem, but the document gives a generic description of NIBS technologies – regardless of their application.
2. The document directly compares uncomparable technologies (for instance transcranial electric (TES) and magnetic (TMS) stimulation), without addressing the differences.
3. The document lists risks that are not relevant for all NIBS technologies (e.g. skin irritation at the electrode site), and risks that are not aligned with the scientific consensus (e.g. seizures).
4. The process in creating the document does not comply with the EU's own regulatory guidelines Better regulation, specifically the two requirements "evidence-based approach" and "participative approach".

Finally, the current reclassification has left an unclear situation where the exact same technology, for instance TMS, is classified both as Class IIa and Class III at the same time – without there being any explanation for why the risks described for a non-medical Class III device would not be equally relevant for a Class IIa medical device.

What can we do?

Our initial efforts in October and November to challenge the reclassification did not stop the December 1st publication. Thus our challenge now is that we have to get the adopted reclassification revoked, amended, or revised to rectify the four main problems listed above. I'm currently involved in the following activities, which anyone can contribute to:
- Engage EU politicians: Every EU state has national representatives in the EU, who were not involved in the process of adopting the reclassification. These politicians can be contacted directly and asked to challenge the reclassification, a list of all representatives can be found here.
- Contact local MDCG members: Each EU member state’s local medical authority has appointed representatives to the Medical Device Coordination Group (MDCG), which is involved in EU regulatory updates, and this group was part of the reclassification. These members can be contacted directly, a complete list is available here.
- Public opinion: for individuals and groups to engage media contacts or publicly express objections to the reclassification – good examples are the ESBS manifesto and this Linkedin post.
- Direct personal letters to the responsible group SANTE.D.3: This ESBS ‘email campaign' is a way to express to SANTE that the 21 replies they received for the hearing were not representative of the number of stakeholders who have opinions about the reclassification. SANTE now has a standard reply for these emails, where they claim no wrongdoing on their end, and say that the only path is to take it to the Court of Justice of the European Union (incorrect). But the more letters they receive the more likely they are to realize they have to reconsider their own process. Furthermore, even if SANTE does not realize the need for a revision, if anyone else is looking into it, it is saying that SANTE got 21 replies on their 'hearing' but then hundred email complaints.
- Formal complaint to the EU Ombudsman: The EU has an appointed Ombudsman, who is tasked with investigating potentially wrongdoing in EU bodies. Based on our claim that SANTE.D.3 has breached two core principles in 'Better Regulation', I have submitted a formal complaint to the EU Ombudsman through their online form. It is a requirement to provide "evidence that you have contacted the relevant institution or body to seek redress must be annexed to the complaint form. Otherwise, you will be informed that we cannot deal with your complaint." so this option is only possible after having received a reply/rejection from SANTE.

The last resort is to initiate a legal case with the Court of Justice of the European Union (CJEU), who can decide to annul a legal act. Additional information on the procedure can be found on the CJEU website – this will be lengthy and costly, and will require the whole NIBS field to get together to back the case.

What are we trying to achieve?

The first request is for the reclassification to be paused or retracted while the complaints are being assessed. Then, a revised version should be released for hearing, and after the hearing adopted into law. In prioritized order, ideally this revised version should:
1. Make a clear distinction between NIBS technologies, and define them properly (e.g. make a distinction between TMS, LOTES and ECT).
2. List risks and side effects for each technology, based on most recent scientific evidence, and specify any resulting concrete risk classification (Class IIa, IIb, III etc) for each technology.
3. If any of the technologies are to be regulated stricter as a non-medical device than a medical device, so the same technology simultaneously have different regulatory classes for different uses, the rationale for this must be clearly defined in the reclassification.

Link to resources

- link to ESBS manifesto
- template for requesting documents from SANTE
- letters to send to sante-med-dev@ec.europa.eu, please edit as much as you can to fit your context/technology:
        - TES focused template (first version)
        - NIBS general template (updated ESBS edit)
- example of the standard reply to expect from SANTE
- template for Ombudsman complaint text (requires to first have received a negative reply from SANTE)
- to contact local EU politicians directly, search for members per country here
- to contact local MDCG members directly, consult the full list of members

Disclosure

I am the founder, CEO and a shareholder of EU based PlatoScience ApS, reg DK37065226. PlatoScience is the manufacturer of medical TES equipment, and thus as an author I have a strong personal interest in the regulation of NIBS technology in Europe. But since PlatoScience’s focus is medical over non-medical applications of medical transcranial electric stimulation (TES), the company’s future products and compliance with the MDR past its introduction in May 2024 is not dependent on Section 6 of Annex XVI to Regulation (EU) 2017/745) and Section 7 of (EU) 2022/2347 discussed in this article. My main concern, which drives my motivation for the article and the initiatives described within, is that Section 7 of (EU) 2022/2347 is not based on the available scientific evidence and that this error will not only impact non-medical devices but eventually also the regulation of medical devices.

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