Procedure and dossier requirements

If a notified body wants to ask the MEB for advice (consultation procedure) relating to a substance that is an integral part of a medical device, but which would be a medicinal product when used separately, the MEB applies the following procedure.

A notified body must send a request for a CP number to the MEB 3 months prior to the submission of a consultation procedure. You can apply for the CP number (with notification of the active substance and application of the medical device) using the contact form by selecting 'Industry/Trade' > 'Medicinal products for people' > 'Medical device / consultation'. A new CP number is only assigned if it is foreseen that the procedure can actually be scheduled.

The notified body will send the documentation to be submitted for a consultation procedure to the MEB. This documentation corresponds to the dossier requirements which can be found on the EMA website for consultations.

The MEB prefers to receive the dossier digitally via CESP, or with an accompanying letter on a CD/DVD. The MEB does not accept any submissions which are only on paper.

Supplementary to the documentation as described in the EMA document, the MEB would like to highlight the following:

  • The application must be accompanied by a completed application form.

  • In the event of a series of products, an application form must be completed for each individual presentation. If it is considered appropriate by the notified body to include a family of products in one application form, this should be agreed with the MEB first. The contact form can be used for this purpose. If needed, a pre-submission meeting can be arranged. 

  • The notified body is asked to submit a report which verifies the ancillary action of the substance which forms an integral part of the medical device.

  • If the notified body has not yet completed the assessment of suitability, it will be asked to publish a provisional opinion about the aspects which have been already assessed and to submit an overview of the outstanding ones (for example a biocompatibility investigation). N.B. This provisional opinion should be stated on the request form.

  • Module 2 is expected to contain a clinical summary which focuses on a discussion of the clinical usefulness of the integral substance, on the functioning of the medical device and on the safety of this substance.

  • In module 1 a declaration from the manufacturer of the medical device must also be submitted stating that the integral substance has been produced under Good Manufacturing Practices (GMP) requirements. It is recommended that this declaration be drawn up in line with the QP declaration.

  • It is preferable for non-clinical and clinical documentation to be drawn up in Dutch or English.

  • In the case of substances of animal origin, attention must be paid to viral safety and the risk of transfer of transmissible spongiform encephalopathies (TSE) to humans.

  • It is preferable for literature references which are submitted to substantiate the quality and safety of the substance, including the benefits/risks of the integral substance in the medical device, to be submitted in separate documents (PDFs).

  • All clinical data submitted by the manufacturer of the medical device to the notified body must be provided. However, the clinical data which is not directly important for substantiating the safety and usefulness of the integral substance must be added exclusively as an annex to the clinical documentation.

  • The quality of the submitted documents. Documents should be textfiles (for example, MS Word) or ‘searchable’ Pdf-files whenever possible.

Transfer

In order to be eligible, a notified body must submit an application for a CP number to the MEB 3 months prior to the transfer. You can apply for the CP number (with notification of the active substance and application of the medical device) using the contact form by selecting 'Industry/Trade' > 'Medicinal products for people' > 'Medical device / consultation'. Each application will be assessed to see if it can be processed.

In the event of a transfer the MEB needs the following documents:

  • The change to consulted medicines agency form
  • The complete existing dossier for which a positive opinion has been issued.

  • A copy of the assessment reports drawn up by the original agency.

  • Proof of CE certification.

  • An overview of all changes following the initial consultation procedure. For each change an indication must be given as to whether and which opinion the original agency has issued. In addition, the type of change (see variations) and the date on which it was approved should be provided.

  • All information on adverse reactions/calamities as reported to the original agency. The MEB will only carry out an administrative check when a transfer takes place.

Reconsultation

The term 'reconsultation' is to be interpreted as a consultation procedure for medical devices with an integral substance under the MDR, for medical devices which have been under the Medical Device Directive 93/42/EEC (MDD). The notified body must submit all documentation (including the Instruction for Use) as stated in the regulation, as well as all changes under the MDD with the outcome of the assessment. The overview of changes should contain the ‘type’ of variation (see variations) and the date on which the change was approved. 

If there have not been any changes, the notified body must submit a declaration to that effect. If only administrative changes have been made, this must be explicitly reported.

Introduction of new aspects to the dossier within a MDR reconsultation is in principle not acceptable. Such changes should be submitted via variations, if minor this is still possible under MDD (see MDCG 2020-3). This should be done prior to the MDR reconsultation. If the variation is not minor, you should submit the change after the MDR reconsultation.

If the time frame does not allow to submit variations before or after the reconsultation, you can submit a request for initial consultation for devices previously assessed under MDD as well. In the initial consultation procedure, the MEB can assess the device, including  ‘new’ variations considering the previous assessment under MDD.  

In addition, ‘related devices’ (family of devices) which have not undergone a (positive) MDD consultation procedure at the MEB before, should follow an individual initial consultation procedure and can not be included within a MDR reconsultation procedure.

The request is to announce 3 months in advance that a reconsultation will be submitted. And, in line with pharmaceutical legislation, submit the documentation for the reconsultation procedure at least 9 months before the certificate expires. During the consultation the quality, safety and usefulness of the integral substance must be assessed, with the assessment under the MDD being taken into account. As a result, this assessment will be less extensive in line with the assessment of a renewal of medicinal products.

With regard to the quality dossier, a declaration from the manufacturer of the medical device must also be submitted stating that the integral substance has been produced under Good Manufacturing Practices (GMP) requirements. The non-clinical and clinical assessment of the benefits and risks will involve looking at the claim which the company is making in the device's Instructions for Use.

Pharmacovigilance will become involved at the moment that there are problems with the safety of an existing medicinal product that has been integrated into the medical device. Moreover, the clinical experience of the medicinal product will be included in the assessment in the event of a reconsultation.

Validation

The dossier is validated after receipt. This means that a check is carried out to determine whether all the required documents are actually present and whether the dossier complies with the aforementioned dossier requirements. An assessment must also take place to determine whether the medical device and the integral substance comply with the stipulations in Article 1, paragraph 8 of the MDR. In particular the usefulness of the integral substance must support the medical device and must be subordinate and not dominant.

If the declaration that the integral substance is produced in accordance with GMP requirements is missing, this will not delay the start of the assessment. A declaration must have been submitted before the second round is restarted.

If the notified body has not received any validation comments within 2 weeks after submission, the procedure will start automatically. If the dossier is invalid, the notified body will be informed within 2 weeks about which documentation and/or information is missing and will be given the opportunity to submit more detailed documentation and information as soon as possible. This may result in the dossier being declared valid after all, to which the assessment period will start. As far as a variation is concerned, the documentation must be submitted in line with the variation regulation EC/1234/2008.

Assessment deadlines

The following assessment deadlines apply:

Known substances with known applications* National consultation procedure for medical devices with a new substance or known substance with new application*  Variations**
Validation -14 days -14 days -14 days

First assessment round

 70 days

70 days

40 days

Second assessment round

 70 days

70 days

20 days

Additional round

 70 days

70 days

-

New substances: those substances which, at the time of the consultation request, are not present as an active substance in any authorised medicinal product in the Netherlands. By contrast, known substances are substances which, at the time of the consultation request, are present as an active substance in one or more authorised medicinal products in the Netherlands. If the medical ground referred to in the consultation procedure concerns a new therapeutic field compared to the medical grounds for which the latter medicinal products were authorised, this will be a new application in connection with a known substance. If a consultation request concerns a series of products, the MEB may decide to charge the payable amount on a one-off basis. The notified body must submit a substantiated request for this.

Variations: all changes relating to the 'quality, safety or benefit/risk' of the substance which forms an integral part of the medical device, but which would be a medicinal product when used separately and whereby a consultation with a competent authority has already taken place for this substance and the product is certified. A number of changes can be foreseen which are so far-reaching that the product must be assessed as a new medical device. The deadlines for variations referred to here apply as long as the MDD is still valid.

***Two rounds of assessment policy for national procedures.

Assessment phase

The requested advice is issued in writing. It includes one or more (sub)reports and an accompanying letter with a recommendation following from the enclosed (sub)report(s). This recommendation may be:

  • A positive opinion that the quality, safety and benefit/risk of the substance has been sufficiently demonstrated in accordance with the standards applied by law when the medicinal product is authorised

  • A request for additional information

  • Advice in which the MEB indicates that a clinical effect of the substance on the patient is improbable, but does indicate that no serious risks are expected and that the quality of the substance is acceptable

  • After the 2nd round, a negative opinion that the quality, safety and/or benefit/risk of the substance has been insufficiently demonstrated in accordance with the standards applied by law when the medicinal product is authorised.

A request to extend the response deadline is possible and must be submitted in writing. If additional information is not received by the stated deadline, the quality, safety and benefit/risk of the substance will be considered to be insufficient and the consultation will be regarded as ended.

The point of departure is that the MEB will issue definitive opinion after no more than two assessment rounds. Exceptions in the form of an extra (third) assessment round are possible, as a result of new information which the MEB has found out about (for example during a hearing or via a written opinion). The latter is at the discretion of the MEB. In the event of a positive or negative opinion (after the 2nd round) the consultation will be regarded as ended.

After the procedure has started (after the dossier has been declared valid), the notified body can retract the request for a consultation with the MEB at any time and ask a different competent authority for advice. In that case the MEB must be informed of the name of the new competent authority. Any withdrawal of a consultation request must be communicated in writing to the MEB immediately. Any payment already made will not be refunded. If there are any outstanding invoices, the requested payment will still be due.

For more information about the consultation procedure at the MEB you can contact the pharmacotherapeutic group under which your products falls.

Negative opinion (after the second assessment round of the consultation procedure)

In the event that, after two assessment rounds of the consultation procedure, serious reservations continue to exist and the MEB therefore intends to issue a negative opinion, the option will be offered to take part in a hearing. This will allow the notified body to present its viewpoint on the situation. If the notified body wishes, it can invite the manufacturer of the medical device in question to accompany it to the meeting. A viewpoint can also be submitted in writing.

The MEB will then issue definitive opinion.