Guidance on the clinical investigation process

I. Definitions

- MDR is defined as a clinical investigation, a systematic study involving one or more people to evaluate the safety or performance of a device.

- Clinical investigational device, any device that is being evaluated in a clinical investigation.

- Clinical investigation plan: a document that describes the rationale, objectives, design, methodology, follow-up, statistical considerations, organisation and conduct of a clinical investigation.

- Sponsor means any person, company, institution or organisation that takes responsibility for initiating, managing and determining the funding of a clinical investigation.

- The subject, the individual participating in the clinical trial.

- An investigator is the individual responsible for conducting a clinical trial at a clinical investigation site.

- Informed consent is the free and voluntary expression by the subject, after having been informed of all aspects of the clinical investigation that are relevant to the subject's decision to participate in the clinical investigation, of his/her wish to participate in that clinical investigation and, in the case of minors and subjects with reduced capacity or incapacity, the authorisation or consent of their legal representative to their inclusion in the clinical investigation.

- Ethics Committee, an independent body established in a Member State in accordance with national law, which is empowered to give an opinion in the application of the MDR, taking into account the views of lay persons, in particular patients and patient organisations. In Hungary, this is the Scientific and Research Ethics Committee of the Scientific Council for Health (ETT TUKEB). Its opinion must be attached to the application for a trial as a condition for the granting of a study authorisation. For details on the application for an ethics opinion, the procedure for obtaining an opinion and the fees, please visit the official website of the ETT TUKEB: https://ett.aeek.hu/tukeb/

The MDR refers to all medical research on human subjects involving medical devices and their accessories as clinical investigations.

II. Clinical investigation types under the MDR

1. Clinical investigations under Article 62(1) of the MDR:

These include clinical investigations conducted to demonstrate the conformity of a medical device/accessory - i.e. clinical investigations with devices intended for clinical investigation. This is a study carried out prior to, and in order to obtain CE marking. This study is subject to authorisation. Also includes clinical investigations where the purpose of the clinical investigation is to further evaluate a device outside the intended purpose of the device (preclinical investigation prior to the introduction of a new indication, to demonstrate this) which already bears the CE marking (Article 74(2) MDR).

Clinical investigations shall be designed, authorised, conducted, recorded and reported in accordance with the provisions of this Article and of Articles 63 to 80, the acts adopted pursuant to Article 81, and Annex XV, where carried out as part of the clinical evaluation for conformity assessment purposes, for one or more of the following purposes:

a) to establish and verify that, under normal conditions of use, a device is designed, manufactured and packaged in such a way that it is suitable for one or more of the specific purposes listed in point (1) of Article 2, and achieves the performance intended as specified by its manufacturer;

b) to establish and verify the clinical benefits of a device as specified by its manufacturer;

c) to establish and verify the clinical safety of the device and to determine any undesirable side effects, under normal conditions of use of the device, and assess whether they constitute acceptable risks when weighed against the benefits to be achieved by the device.

The clinical investigations referred to here may only be conducted if all the conditions listed in Article 62(4) of the MDR are met.

Devices intended for clinical investigation may not bear the CE marking¹ but the words "for clinical investigation only" must appear on the device and in its instructions for use.

A clinical investigation is subject to authorisation under Article 62 of the MDR, and the application for authorisation must be submitted to the NNGYK before EUDAMED becomes operational. It should be stressed that the ethical opinion of the ETT TUKEB must be attached to the application, in addition to the proof of payment of the administrative service fee; in the case of a negative, non-supportive opinion of the ethics committee, no investigation authorisation may be granted.

In the case of clinical investigations under Articles 62(1) and 74(2) of the MDR, the provisions of Government Decree No 33/2009 (X. 20. ) of the Ministry of Health and the provisions of Regulation (EC) No 235/2009 (20. X.) 3. title of the Government on the rules of the authorisation procedure for the clinical investigation of medical devices intended for clinical investigation in human beings, clinical investigation of investigational medicinal products for human use and clinical investigation of medical devices intended for human use also apply in addition to the provisions of the MDR.

¹ Unless a device already CE marked is being tested for a new indication, in which case the indication still being tested is not covered by the CE marking, so this should not be indicated in the instructions for use!

2. Clinical trials under Article 74(1) of the MDR

Also known as post-marketing clinical follow up studies (PMCF studies), these are referred to in Hungarian national legislation as "non-interventional studies". In this case, the purpose of the investigation is the further evaluation of a device within the intended use of the device, which already bears the CE marking, and the subjects are subjected to procedures that are invasive or burdensome in addition to those performed during the normal use of the device. These investigations are subject to mandatory notification.

Post-market clinical follow-up studies (PMCF studies) are based on the post-market surveillance plan included in the technical documentation of the medical device.

Such clinical investigations must be designed, conducted, recorded and reported in accordance with the MDR provisions and Annex XV if they are conducted as part of a clinical evaluation for conformity assessment purposes for one or more of the following purposes:

a) to verify that the design, manufacture and packaging of the device, under normal conditions of use, are such as to enable it to fulfil one of the intended purposes listed in Article 2(1) and to achieve the intended performance specified by its manufacturer;

b) verification that the clinical benefits of the device correspond to those claimed by its manufacturer;

c) to verify the clinical safety of the device and to determine any undesirable side-effects which may occur during use under normal conditions of use and to assess whether they represent an acceptable risk in relation to the benefits of the device.

Clinical investigations/post-marketing clinical follow-up studies (PMCFs) under Article 74 of the MDR may only be conducted if the requirements of Article 62(4)(b) to (k) and (m) of the MDR and Annex XV are met. In addition, the provisions of Articles 15-21 of Government Decree No. 235/2009 (X. 20.) on the rules of the authorisation procedure for medical research involving human subjects, clinical trials of investigational medicinal products for human use and clinical trials of medical devices intended for clinical investigation in human subjects and of Decree No. 23/2002 (V. 9.) of the Ministry of Health on medical research involving human subjects are also applicable.

Until EUDAMED is launched, these investigations should be reported directly to the NNGYK via e-Administration. It should be noted that the ETT TUKEB opinion is attached to the notification, together with the receipt for payment of the administrative service fee. In the event of a negative, non-supportive opinion of the Ethics Committee, the investigation cannot be launched.

The provisions of Government Decree 235/2009 (20.X.2009) under Title 3/A shall also apply to the clinical investigation of medical devices intended for human use and intended for clinical investigation which use ionising radiation.

3. Investigations under Article 74(2) of the MDR

If the purpose of the clinical investigation is the further evaluation of a device outside the intended purpose of the device which already bears the CE marking, Articles 62-81 MDR apply in respect of the design, application/"authorisation" and conduct of the investigation (see. Description of clinical investigations under Article 62(1) MDR)

4. Requirements regarding other clinical investigations

Clinical investigations, not performed pursuant to any of the purposes listed in Article 62(1), shall comply with the provisions of Article 62 (2) and (3), points (b), (c), (d), (f), (h), and (l) of Article 62(4) and Article 62(6). For these clinical investigations, in order to ensure the protection of the rights, safety, dignity and well-being of the subjects, on the one hand, and the scientific and ethical integrity of the procedure, on the other, each Member State concerned shall, as appropriate, lay down specific requirements for these trials. These requirements shall be laid down in national legislation.

These investigations are generally considered as non-interventional and are notifiable.

It is worth noting here the coordinated assessment procedure for multicentre clinical investigations under Article 78 of the MDR, which is a separate type of clinical investigation in that the sponsor may submit a single application if it wishes to conduct the trial in more than one Member State. In the consolidated application, the sponsor must propose that one of the Member States where the clinical trial will be conducted be the coordinating Member State, but the coordinating Member State is to be agreed by the Member States concerned.

Of course, all Member States concerned will participate in the assessment of the application, but all Member States concerned will have to take into account the final assessment report issued by the coordinating Member State.The earliest date for this coordinated assessment procedure for multicentre trials in Hungary will be 2027. Until then, the current legislation requires a NNGYK authorisation/notification for multicentre trials at Hungarian sites.

Clinical investigations, including non-interventional investigations, should be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects are protected and take precedence over all other interests, and that the clinical data generated from the investigations are scientifically valid, reliable and robust.

For the clinical investigation of medical devices for human use intended for clinical investigation using ionising radiation (whether clinical investigation under Article 62(1) MDR or Article 74(2) MDR), the provisions of Government Decree No 235/2009 (20.X.2009) under Title 3/A also apply (see also Information Sheet IX).

III. Other general information

The manufacturer of the medical device in a clinical investigation must be registered in the EUDAMED electronic system for the registration of economic operators (Actor module) and have an SRN number, according to Article 30 of the MDR, and the manufacturer of the device intended for a clinical investigation is no exception. Without this, you will not be able to upload your application to the EUDAMED database. For information on the EUDAMED Actor module and the registration process, please visit https://ogyei.gov.hu/eudamed_actor_modul.

The person responsible for ensuring compliance with the rules (PRRC) must also be responsible for ensuring that the declaration referred to in Annex XV, Chapter II, point 4.1 has been issued for clinical investigations of devices intended for clinical investigation.

EUDAMED includes the electronic system for clinical investigations referred to in Article 73 of the MDR. Until this module is operational, applications should continue to be submitted directly to the NNGYK via e-Administration⁎. As soon as EUDAMED is operational, applications/notifications will be submitted to the NNGYK via e-Administration.

Information on e-Administration can be found at the following link: https://ogyei.gov.hu/eugyintezes If the size of the documentation to be attached to the application so requires, it is possible to send the annexes via the transfer system, in addition to the application sent via eadministration, at the following interfaces: https://transfer.ogyei.gov.hu/verify.php and https://transfer.ogyei.gov.hu/changelocale.php (please enter igazgatas.iroda@nngyk.gov.hu for the NNGYK in this transfer interface)

The general requirements for the design and conduct of clinical investigations (ethical principles and methods of trial conduct) are set out in Chapter I of Annex XV of the MDR.

From the initial consideration of the need for and justification of a clinical investigation to the publication of the results, each step of the clinical investigation must be conducted in accordance with recognised ethical principles (e.g. Declaration of Helsinki [DoH]1 , Code of Medical Ethics, Code of Ethics of the Hungarian Chamber of Health Care Professionals), the MDR and ISO 14155:2020 (Human clinical trials of medical devices. Good clinical practice) (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/)

Ethics Committee, an independent body established in a Member State in accordance with national law, which is empowered to give an opinion in the application of the MDR, taking into account the views of lay persons, in particular patients and patient organisations. In Hungary, this is the ETT TUKEB. Its ethical opinion must be attached to the application.

IV. Submission of the application/notification and the basis for the regulatory procedure for clinical investigations under Articles 62-74-82 of the MDR

1. Obtaining a positive ethical opinion

In all cases (including modification), investigations should be subject to scientific and ethical review. The ethical review should be carried out by an ethics committee. In the case of clinical investigations, non-interventional investigations or applications/notifications for substantial modifications, a copy of the opinion or opinions of the competent ethics committee (Scientific and Research Ethics Committee of the Scientific Council for Health, hereinafter referred to as the 'Scientific Committee on Ethics') must be attached to the application. Such an ethics opinion must be requested from the ETT TUKEB prior to the procedure before the NNGYK. For details on the application for an ethics opinion and the procedure for obtaining one, please visit the official website of the ETT TUKEB: https://ett.okfo.gov.hu/tukeb/

2. Conditions and history of the application

● If the sponsor of the clinical investigation is not established in the Union, care must be taken to ensure that a natural or legal person established in the Union acts as its legal representative in the Union (Article 62(2) MDR).

● The manufacturer established in Hungary or the manufacturer with an authorised representative established in Hungary, the authorised representative established in Hungary must be registered with EUDAMED according to Article 31 of the MDR, must have an SRN number. In any case, the manufacturer of the device intended for clinical investigation must have an SRN number: https://ogyei.gov.hu/medical_devices

● If an economic operator established in Hungary and manufacturing a custom-made device intends to conduct a clinical investigation, it must prove that it has fulfilled its notification obligation pursuant to paragraph (2) of Article 17 of Decree 4/2009 (III.17.) of the Ministry of Health.

● The sponsor of the clinical investigation must submit an application/notification to the Medical Device Authority (MDA) of the Member State where the clinical investigation is being conducted.

● The application/notification must be submitted via the electronic system referred to in Article 73 of the MDR (EUDAMED clinical trial module). As long as the EUDAMED "clinical trials module" is not operational, the NNGYK will only accept applications via e-Administration* (see also: II. Additional general information).

● The EUDAMED system must generate a unique EU-wide identification number (CIV-ID) for a clinical trial, which must be provided in all communications related to the clinical trial. As long as the EUDAMED 'clinical trials module' is not operational, the NNGYK will register the clinical trial in EUDAMED2 and send the ID received there to the sponsor (MDCG 2021-20).

*According to Act CCXXII of 2015 on the General Rules of Electronic Administration and Trust Services (e-Administration Act), from 1 January 2018, it is mandatory for business organisations to communicate electronically with certain public authorities and to send/receive documents via the official contact details required for this purpose. Help for starting an official case can be found at the following link: https://ogyei.gov.hu/eugyintezes

3. Application/notification and documents to be submitted

The official EU website provides the MDCG 2021-08 guidance document, which contains the application/notification forms for clinical investigations on medical devices, available at the link below:

https://ec.europa.eu/health/sites/default/files/md_sector/docs/mdcg_2021-8_en.pdf

For the application/notification, the forms in the MDCG Guide 2021-08 should be used, and of course the content and additional documentation required in Annex XV, Chapter II of the MDR should be attached.

The full documentation includes the following, please include the documents in italics in Hungarian (NNGYK requirements, MDR 2017/745 Articles 62, 74, 82 and Annex XV. checklist):

Please submit the documents in a folder, zipped and numbered according to the List of annexes document!

Please complete the " Melléklet lista/ List of annexes " document and attach it to the application in docx format:

https://ogyei.gov.hu/dynamic/melleklet_lista_list_of_annexes.docx

For the clinical investigation of medical devices for human use intended for clinical investigation using ionising radiation (whether clinical investigation under Article 62(1) of the MDR or Article 74(2) of the MDR), the requirements of Government Decree 235/2009 (20.X.2009) under Title 3/A also apply, so the scope of the documents to be submitted is extended in this case (see Information Sheet IX).

Please note that the documents to be submitted are those listed here for the purposes of the application/notification, but will be assessed on the basis of the content of the documents submitted in accordance with the requirements of the MDR and ISO 14155:2020.

4. Authority procedure, evaluation

The authorisation procedure for clinical investigations conducted under the MDR is not subject to the previously established procedural deadlines set out in Act CL of 2016 on the General Administrative Procedure (General Administrative Procedure). The timeframes for the receipt and assessment of applications/notifications for clinical trials under the MDR are those set out in the MDR.

If the time given to the Client to complete the application/notification documents is not sufficient, the Client may request the suspension of the procedure pursuant to Article 49 of the General Civil Procedure Code. The procedure shall be resumed at the request of the client, with the proviso that after the six-month pause, the procedure, which can only be resumed upon request, shall be terminated, and the authority shall notify the Principal of the fact of termination.

a. In the case of investigations under Article 62(1) of the MDR:

Within ten days of receipt of the application, the NNGYK will notify the sponsor whether the clinical investigation falls within the scope of the MDR and whether the documentation is complete as described in Annex XV, Chapter II.

If the NNGYK determines that the clinical investigation that is the subject of the application does not fall within the scope of the MDR or that the documentation is incomplete, it will inform the sponsor accordingly and set a time limit of up to ten days for the sponsor to comment on or complete the application via the electronic system. This can be considered as a possibility to remedy the deficiencies as known from the past. This period may be extended by the NNGYK up to a maximum of 20 days where appropriate (this requires a request for an extension to be submitted within the deadline).

Then, based on the answer, the first process is completed with the following options:

● If the sponsor has not commented on or completed the application within this 10-day period (+20 days in the case of an application), the application shall be declared terminated.

● If the sponsor considers that the application falls within the scope of the MDR and/or that the application and its documentation are complete, but the Member State concerned does not agree, the application shall be considered as rejected. The NNGYK shall provide an appeal procedure against such a negative decision.

● If the NNGYK accepts the sponsor's response and/or the supplement to the application dossier, the NNGYK will notify the sponsor within five days of receipt of the comments or the requested supplementary information whether the clinical investigation is considered to be within the scope of the MDR and whether the application is complete. (An additional extension of 5 days may be granted by the authority.) In light of this, the date on which the sponsor is notified by the NNGYK that the clinical trial is considered to be within the scope of the MDR and that the application is complete should be considered the date of validation of the application.

After the validation date, the NNGYK must carry out an assessment as detailed in Article 71 of the MDR, for which it has 45 days, or may extend it for an additional 20 days for expert consultations! Please note that the study can only be started once the approval decision has been issued by the NNGYK.

b. For investigations under Article 74(1) of the MDR

In a post-marketing clinical follow-up study, if the study involves subjects undergoing procedures that are invasive or burdensome in addition to those performed during the intended use of the device, the sponsor must be notified at least 30 days before the start of the study.

Please note that if the notification is incomplete or inadequate in content, the investigation may not commence until the 30th day after the date of the complete supplement to the certificate of registration.

c. For investigations under Article 74(2) of the MDR

The procedure is the same as for inspections under Article 62(1) of the MDR, see point (a).

d. In the case of investigations under Article 82 of the MDR

The procedure is the same as for investigations under Article 74(1) of the MDR, see point (b). If the device subject to such a clinical investigation has not yet been CE marked, the procedure under point (a) shall apply.

For the clinical investigation of medical devices using ionising radiation intended for human use in clinical trials (whether clinical investigation under Article 62(1) of the MDR or Article 74(2) of the MDR), the provisions of Government Decree 235/2009 (X.20.) under Title 3/A also apply, so the NNK is requested as the competent authority in the authorisation procedure. Pursuant to Section 37/C (1) of Government Decree No. 235/2009, the licensing authority (NNGYK) shall also obtain the opinion of the National Medical Officer in the course of the licensing of research for the clinical investigation of medical devices for human application using ionising radiation intended for clinical investigation (pursuant to Section 37/B (1) of Government Decree No. 235/2009) (see Information IX).

5. Authority decision (authorisation, registration)

At the end of the regulatory procedure for the assessment of an application for a clinical investigation, an "authorisation" / "authorisation decision" is not always issued, but there are circumstances in which a clinical investigation may be started. When a clinical trial can start and whether an authorisation is required depends on the risk classification of the medical device involved in the clinical trial and the invasiveness of the healthcare provided during the clinical investigation, as well as the outcome of the assessment detailed by the NNGYK in Article 71 of the MDR.

Approval:

The sponsor may commence clinical investigations under Articles 62(1) and 74(2) of the MDR under the following circumstances, in accordance with Article 70(7) of the MDR:

a) For a Class I device intended for clinical investigation, or for a Class IIa or IIb non-invasive device, clinical investigation may be started immediately after the date of validation of the application, unless otherwise provided for in national law. Provided that the competent ethics committee ("ETT TUKEB") has not issued an unfavourable opinion on the clinical trial. In these cases, the evaluation procedure under Article 71 of the MDR is also carried out by the NNGYK.

Please note that according to § 1 (3) and § 16 (1) of the Decree 33/2009 (X.20.) of the Ministry of Health, the clinical investigation may be continued according to the conditions set out in the letter of the authorisation decision and the conditions set out in the decision and the provisions of the authorised protocol.

b) In the case of devices other than those referred to in point a) (i.e. Class IIa or IIb invasive devices, Class III devices and implants) and devices intended for clinical investigation, once the sponsor has been notified by the NNGYK of the authorisation (which will be issued within 45 days of the validation date, during which time the NNGYK will conduct the MDR 71. Provided that the relevant ethics committee ("ETT TUKEB") has not issued an unfavourable opinion on the clinical trial, the NNGYK may extend the 45-day time limit by a further 20 days for expert consultations!

Clinical investigations pursuant to Articles 62(1) and 74(2) of the MDR may be conducted only if all of the following conditions are met:

a) unless otherwise specified, the clinical investigation shall be authorised by the Member State(s) in which the investigation is to be conducted in accordance with this Regulation;

b) an ethics committee set up in accordance with national law has not issued an unfavourable opinion on the clinical investigation which is valid for the whole of the Member State concerned in accordance with national law;

c) the sponsor or his legal representative or contact person as referred to in Article 62(2) is established in the Union;

d) vulnerable populations and subjects are adequately protected in accordance with Articles 64 to 68;

e) the foreseeable risks and inconveniences are acceptable in view of the benefits to subjects and public health and compliance with this condition is monitored on an ongoing basis;

f) informed consent has been given by the subject or, where the subject is unable to give informed consent, by his legal representative, in accordance with Article 63;

g) the subject or, if the subject is not able to give informed consent, the legal representative of the subject has been informed of the contact details of the organisation from which he or she may obtain further information, if necessary;

h) the subject's rights to physical and mental integrity, privacy and data protection with respect to the subject have been ensured in accordance with Directive 95/46/EC;

i) the clinical investigation is designed to cause the least possible pain, discomfort, fear and any other foreseeable risk to the subject in relation to the disease, and both the risk threshold and the level of exposure are clearly defined in the clinical investigation plan and monitored continuously;

j) the medical care provided to subjects is the responsibility of a suitably qualified medical or, where appropriate, dental practitioner or other person who is authorised under national law to provide relevant patient care under clinical investigation conditions;

k) no undue influence, including financial influence, is exerted on the subject or, where applicable, on his legal representative, in order to participate in the clinical investigation;

l) the device(s) in question intended for the clinical investigation complies with the general safety and performance requirements set out in Annex I, except for the aspects which are the subject of the clinical investigation, and that all precautions have been taken with regard to these aspects to protect the health and safety of the subjects. This includes, where appropriate, technical and biological safety studies and pre-clinical evaluation, as well as safety at work and accident prevention

m) the requirements of Annex XV are met.

Certificate of registration:

In the case of a clinical investigation under Article 74(1) of the MDR, if the notification and the trial dossier are adequate (subject to the outcome of the assessment by the Member State under Article 71 of the MDR), the NNFCA will issue a certificate of authorisation. According to Article 17(1)(c) of Government Decree No 235/2009 (20.X.), in the case of the investigations referred to in Article 16(b), the investigation may be conducted in possession of a certificate issued by the NNGYK on the subject of the notification.

V. The substantial modifications to clinical invesztigations conducted under the MDR

According to Article 35 (1) of Government Decree 235/2009 (X.20), the following changes to clinical investigations are considered substantial modifications, which must be conducted in accordance with MDR 75:

a) the change relates to the purpose, circumstances or mechanism of action of the device,

b) the amendment may change the interpretation of the scientific documents supporting the conduct of the trial,

c) the amendment affects the Investigator's Brochure,

d) the results of the study to date require a change to the written information; or

e) the amendment may affect the safety, health or rights of subjects.

Please note that any changes and/or modifications to the data contained in the decision authorising the clinical investigation or the decision confirming registration (e.g. trial site, investigator, sponsor, number of subjects enrolled, trial duration, etc.) must also be reported to the NNGYK.

How and when to change:

If the sponsor intends to modify a clinical investigation in such a way that it can be considered a substantial modification, it must clearly indicate the change to the documentation. He must also notify the Member State(s) where the clinical investigation is being or will be conducted of the reasons for and nature of the modification within one week via the EUDAMED 'clinical investigations module'. As long as the EUDAMED 'clinical investigations module' is not operational, the NNGYK will receive requests or notifications of amendments via e-administration.

Application and documents to be submitted:

As part of the notification, the sponsor must include an updated version of the relevant documentation referred to in Annex XV, Chapter II, along with the forms in MDCG Guide 2021-08 and the modification form in MDCG Guide 2021-28. The relevant documentation shall clearly indicate the modifications.

An accompanying form for the notification of changes has been created by the EU and is available at the link below:

https://ec.europa.eu/health/system/files/2021-12/mdcg_2021-28_annex_1_en.pdf

Or can be found in the Annex to MDCG Guideline 2021-28:

https://ec.europa.eu/health/system/files/2022-01/mdcg_2021-28_en.pdf

In addition to the receipt for the payment of the administrative service fee, the ETT TUKEB ethical opinion is attached to the amendment application/notification. In the case of a negative, non-supportive opinion of the Ethics Committee, no modification of its authorisation/registration can be made.

For the clinical investigation and modification of medical devices for human use intended for clinical investigation using ionising radiation (whether clinical investigation under Article 62(1) of the MDR or Article 74(2) of the MDR), the provisions of Government Decree 235/2009 (20.X.2009) under Title 3/A also apply, so the scope of the documents to be submitted is extended in this case (see Information Sheet IX).

The official procedure for approving an modification:

The NNGYK will consider any substantial amendment to a clinical investigation in accordance with the procedure set out in Article 71 of the MDR.

For clinical investigations and modifications of medical devices using ionising radiation intended for human use in clinical trials (be it a clinical trial under Article 62(1) of the MDR or a clinical trial under Article 74(2) of the MDR), the provisions of Government Decree 235/2009 (20.X.2009) under Title 3/A also apply, so the NNK is requested as the competent authority in the authorisation procedure (and the procedure for the authorisation of the modification). Pursuant to Section 37/C (1) of Government Decree No 235/2009, when authorising research or modifications to research for the clinical investigation of medical devices for human use using ionising radiation intended for clinical investigation (pursuant to Section 37/B (1) of Government Decree No 235/2009), the authorising body (NNGYK) also obtains the opinion of the competent authority of the National Medical Officer (see Information Sheet IX).

When can a modified clinical investigation start:

The sponsor may start the clinical investigation no earlier than 38 days after the notification of the amendments in EUDAMED (currently e-Administration), unless:

● the Member State has notified the sponsor that it has refused the variation (the grounds for refusal may be: Article 71(4) or considerations relating to public health, the safety or health of subjects and users or public policy)

● or, the ethics committee of the Member State concerned has issued an unfavourable opinion on a substantial modification of the clinical investigation which is valid for the whole Member State in accordance with national law.

The Member State(s) concerned by the variation request may extend the period of 38 days referred to in Article 75(3) of the MDR for a further seven (7) days for the purpose of expert consultations.

VI. Recording and reporting adverse events in clinical investigations

The sponsor shall promptly report the following vigilance events in relation to clinical investigations under Article 62(1) of the MDR to the Member States where the clinical investigation is conducted:

● any serious adverse event that is causally related to the device intended for the clinical investigation, the device being compared or the investigational procedure, or for which such a causal relationship can reasonably be assumed;

● any device failure that could have led to a serious adverse event in the absence of appropriate action or intervention or under less favourable circumstances;

● any new finding relating to the events referred to in the preceding points.

These reports can be submitted by the sponsor via the EUDAMED "clinical investigation module" electronic system referred to in Article 73 of the MDR. In the case of Hungary, these reports are expected to be sent by the NNGYK to amd.vig@nngyk.gov.hu (referring to the file number of the clinical investigation authorisation decision and indicating the CIV-ID of the clinical investigation) until the official launch of the EUDAMED "clinical investigation module".

The sponsor must also report adverse events occurring during clinical investigations to the relevant Member States where the clinical investigation is being conducted, and any adverse events occurring in third countries (outside the EU) where a clinical investigation is being conducted under the same protocol as the clinical investigation plan for clinical investigations covered by the MDR.

Guidance on reporting of adverse events in clinical investigations is provided in the MDCG Guide 2020-10/1, which can be accessed via the link below:

https://ec.europa.eu/health/sites/default/files/md_sector/docs/md_mdcg_2020-10-1_guidance_safety_reporting_en.pdf

In addition, the form is available in Excel format at MDCG 2020-10/2:

https://ec.europa.eu/health/md_sector/new_regulations/guidance_en

WARNING! In the case of clinical follow-up referred to in Article 74(1) of the MDR, i.e. post-marketing clinical follow-up, adverse event reporting shall be carried out in accordance with Articles 87-90 and 91 of the MDR. And it must be sent to the Authority via the EUDAMED "vigilance module" electronic system referred to in Article 92 of the MDR. The NNGYK expects vigilance reports to be sent to amd.vig@nngyk.gov.hu until the official launch of the EUDAMED "vigilance module". In the adverse event report, please indicate separately if the adverse event occurred in a clinical investigation under Article 74 of the MDR, in which case the registration number of the clinical investigation authorisation decision/registration document and the CIV-ID of the clinical investigation should be included in the report.

However, if a causal link between the serious adverse event and the PMCF study procedure preceding it is established during the post-marketing clinical follow-up (PMCF/ and non-interventional) study, then Article 80 of the MDR applies to the vigilance report and the report must be submitted to the EUDAMED "clinical investigation module" and the NNGYK is waiting for the submission to amd.vig@nngyk.gov.hu until the module is launched.

Information and forms on the reporting of adverse events involving CE marked medical devices are available on the NNGYK website at the following links:

https://ogyei.gov.hu/varatlan_esemeny_jelentes https://ogyei.gov.hu/varatlan_esemeny_jelentes_formanyomtatvanyok

VII. Rules on the end and interrupts of a clinical investigation

Where the sponsor temporarily interrupts a clinical investigation, it must notify the Member State where the temporary interruption of the clinical investigation took place within 15 days, stating the reasons for the temporary interruption. Where the sponsor has temporarily interrupted a clinical investigation for safety reasons, it must notify all Member States where the clinical investigation is being conducted within 24 hours.

Where the sponsor prematurely terminates a clinical investigation permanently, it shall notify the Member State where the premature termination of the clinical investigation took place within 15 days, stating the reasons for the premature termination. Where the sponsor has prematurely terminated a clinical investigation permanently for safety reasons, it shall notify all Member States where the clinical investigation is being conducted within 24 hours.

The sponsor shall notify each Member State in which the clinical investigation was conducted of the completion of the clinical investigation in that Member State. The notification shall be made within 15 days of the end of the clinical investigation in the Member State concerned.

The end of the clinical investigation shall be considered to be the last investigation of the last subject, unless another date is specified in the clinical investigation plan as the end of the clinical investigation.

The sponsor shall send the notification of the temporary interruption, premature termination or end of the clinical investigation via the EUDAMED electronic clinical investigation system. As long as the EUDAMED 'clinical investigations module' is not operational, the NNGYK will receive these documents via e-Administration.

Irrespective of the outcome of the clinical investigation, within one year of the end of the clinical investigation or within three months of its premature definitive end or temporary interruption, the sponsor must submit a clinical investigation report in accordance with Annex XV, Chapter I, point 2.8 and Chapter III, point 7 of the MDR to the Member States in which the clinical investigation was conducted.

The clinical investigation report shall be accompanied by a summary written in a way that is easily understandable for the target users. The sponsor shall submit both the report and the summary through the EUDAMED electronic clinical investigation system. As long as the EUDAMED 'clinical investigations module' is not operational, the NNGYK will receive these documents via e-filing.

The NNGYK will send the final clinical investigation report submitted to it in relation to clinical investigations on medical devices to the ETT TUKEB.

VIII. Administrative service fees for official procedures relating to clinical investigations

Pursuant to § 101/A of Act CLIV of 1997 on Health Care (Act on Health Care) and § 164/B of the Act on Health Care, an administrative service fee is payable for the procedure for the authorisation or notification of a medical research conducted with a device intended for clinical investigation and for the authorisation or notification of a research not involving an intervention pursuant to § 164/A of the Act on Health Care. For all types of clinical trials with medical devices, proof of payment of the administrative service fee must be provided at the time of the submission of the application/notification, which is a condition for the initiation of the official procedure; failure to pay the fee will result in the rejection of the application/notification.

Authorisation of a clinical investigation of a medical device under Article 62(1) and Article 74(2) of Regulation (EU) No 745/2017 (MDR) and authorisation of a substantial modification to the protocol*	243 000 HUF/ application
In the case of a medical device investigation pursuant to Article 16(b) of Government Decree No. 235/2009 (20.X.), i.e. notification of non-interventional investigations of medical devices and notification of amendments to the investigation plan, pursuant to Articles 74(1) and 82 of the MDR	99 000 HUF/ notification
Authorisation of a clinical trial of a medical device using ionising radiation, authorisation of a substantial modification of the protocol	397 845 HUF/ application

*A fee is payable for each separate, separate and unrelated application for a substantial modification under separate legislation for a variation to a clinical investigation authorisation for a medical device, whether the application is submitted individually or grouped for several studies at the same time.

Financial details for transfer: https://ogyei.gov.hu/penzugyi_adatok_atutalashoz

Name: Nemzeti Népegészségügyi és Gyógyszerészeti Központ

Tax number: 15598787-2-43

Bank: Magyar Államkincstár

Bank location: 1139 Budapest, Hungary, Váci út 71.

Bank account number: 10032000-00290438-00000000

IBAN: HU551003-2000-0029-0438-0000-0000

Please indicate the identifier of the investigation or the address of the investigation in the communication box next to the word "medical device". Please also note that the NNGYK can only invoice the payer of the administrative service fee, for which the NNGYK needs the originator's details and email address.

IX. National rules on the authorisation and modification of clinical investigations of medical devices for human use involving IONISING RADIATION intended for clinical investigation

The provisions of Government Decree 235/2009 (20.X.2009) under Title 3/A shall also apply to the clinical investigation and modification of medical devices for human use intended for clinical investigation using ionising radiation (whether clinical investigation under Article 62(1) of the MDR or Article 74(2) of the MDR). Thus, the NNGYK will be called upon as the competent authority in the authorisation procedure (as well as in the procedure for the authorisation of a variation).

Pursuant to Section 37/C (1) of Government Decree No. 235/2009, when authorising research or modifications of research for the clinical investigation of medical devices using ionising radiation intended for human application in clinical trials (pursuant to Section 37/B (1) of Government Decree No. 235/2009), the authorising body (NNGYK) shall also obtain the opinion of the national medical officer of health.

Radiation health documentation shall be submitted as an annex to the application for the authorisation of a clinical investigation or, in the case of an authorised clinical investigation that is to be modified, for the authorisation of a modification, in accordance with the following content of § 37/C (2) of Government Regulation No. 235/2009:

a) "the establishment of individualised dose levels for research subjects,

b) the determination of dose multiplication for caregivers and assistants and for research participants,

c) information of particular importance for the radiological protection of research subjects:

● their sex,

● their age,

● their age, pregnancy and conception,

● the measures taken to optimise their exposure,

● the fact that they have participated in previous research programmes involving exposure,

d) information on the investigators and the healthcare provider conducting the research:

● If the research is conducted by a person licensed to use nuclear energy, a copy of the licence to use radioactive material or to operate a facility that generates ionizing radiation but does not contain radioactive material, and a copy of the radiation protection policy and radiation protection description of the workplace,

● requirements for the professional and radiation protection qualifications of those planning, approving and performing irradiation under the direction of the investigator,

e) a risk assessment describing the estimated exposure of subjects, investigators, caregivers and helpers and the general public to ionising radiation during the research”

For the purposes of Title 3/A of Government Decree 235/2009, the following definitions and terms shall apply to clinical trials under the MDR for the clinical investigation of medical devices for human use intended for clinical investigation and using ionising radiation:

- Caregivers and helpers are persons who knowingly and intentionally expose themselves to ionising radiation while assisting in the care and support of persons who are or have been medically exposed outside their job duties.

- Research workers are those persons employed by the health care provider conducting the research who are involved in the research and for whom an occupational exposure dose multiplication is to be established under the Government Decree on Protection against Ionising Radiation and the Related Licensing, Reporting and Control System.

- For other definitions, the definitions set out in Article 4(1) of Government Decree No. 487/2015 (XII. 30.) on Protection against Ionizing Radiation and the Related Licensing, Reporting and Control System shall be taken into account:

https://net.jogtar.hu/jogszabaly?docid=A1500487.KOR&txtreferer=99600116.TV