Requirements regarding other clinical investigations
1. 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).
2. In order to protect the rights, safety, dignity and well-being of subjects and the scientific and ethical integrity of clinical investigations not performed for any of the purposes listed in Article 62(1), each Member State shall define any additional requirements for such investigations, as appropriate for each Member State concerned.
The Commission may, by means of implementing acts, establish the detailed arrangements and procedural aspects necessary for the implementation of this Chapter as regards the following:
(a)
harmonised electronic forms for the application for clinical investigations and their assessment as referred to in Articles 70 and78, taking into account specific categories or groups of devices;
(b)
the functioning of the electronic system referred to in Article 73;
(c)
harmonised electronic forms for the notification of PMCF investigations as referred to in Article 74(1), and of substantial modifications as referred to in Article 75;
(d)
the exchange of information between Member States as referred to in Article 76;
(e)
harmonised electronic forms for the reporting of serious adverse events and device deficiencies as referred to in Article 80;
(f)
the timelines for the reporting of serious adverse events and device deficiencies, taking into account the severity of the event to be reported as referred to in Article 80;
(g)
uniform application of the requirements regarding the clinical evidence or data needed to demonstrate compliance with the general safety and performance requirements set out in Annex I.
The implementing acts referred to in the first paragraph shall be adopted in accordance with the examination procedure referred to in Article 114(3).
Recording and reporting of adverse events that occur during clinical investigations
1. The sponsor shall fully record all of the following:
(a)
any adverse event of a type identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation;
(b)
any serious adverse event;
(c)
any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate;
(d)
any new findings in relation to any event referred to in points (a) to(c).
2. The sponsor shall report, without delay to all Member States in which the clinical investigation is being conducted, all of the following by means of the electronic system referred to in Article 73:
(a)
any serious adverse event that has a causal relationship with the investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible;
(b)
any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate;
(c)
any new findings in relation to any event referred to in points (a) and (b).
The period for reporting shall take account of the severity of the event. Where necessary to ensure timely reporting, the sponsor may submit an initial report that is incomplete followed up by a complete report.
Upon request by any Member State in which the clinical investigation is being conducted, the sponsor shall provide all information referred to in paragraph 1.
3. The sponsor shall also report to the Member States in which the clinical investigation is being conducted any event referred to in paragraph 2 of this Article that occurred in third countries in which a clinical investigation is performed under the same clinical investigation plan as the one applying to a clinical investigation covered by this Regulation by means of the electronic system referred to in Article 73.
4. In the case of a clinical investigation for which the sponsor has used the single application referred to in Article 78, the sponsor shall report any event as referred to in paragraph 2 of this Article by means of the electronic system referred to in Article 73. Upon receipt, this report shall be transmitted electronically to all Member States in which the clinical investigation is being conducted.
Under the direction of the coordinating Member State referred to in Article 78(2), the Member States shall coordinate their assessment of serious adverse events and device deficiencies to determine whether to modify, suspend or terminate the clinical investigation or whether to revoke the authorisation for that clinical investigation.
This paragraph shall not affect the rights of the other Member States to perform their own evaluation and to adopt measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. The coordinating Member State and the Commission shall be kept informed of the outcome of any such evaluation and the adoption of any such measures.
5. In the case of PMCF investigations referred to in Article 74(1), the provisions on vigilance laid down in Articles 87 to 90 and in the acts adopted pursuant to Article 91 shall apply instead of this Article.
6. Notwithstanding paragraph 5, this Article shall apply where a causal relationship between the serious adverse event and the preceding investigational procedure has been established.
By 27 May 2026, the Commission shall submit to the European Parliament and to the Council a report on experience gained from the application of Article 78 and, if necessary, propose a review of Article 78(14) and point (h) of Article 123(3).
Coordinated assessment procedure for clinical investigations
1. By means of the electronic system referred to in Article 73, the sponsor of a clinical investigation to be conducted in more than one Member State may submit, for the purpose of Article 70, a single application that, upon receipt, is transmitted electronically to all Member States in which the clinical investigation is to be conducted.
2. The sponsor shall propose in the single application referred to in paragraph 1 that one of the Member States in which the clinical investigation is to be conducted acts as coordinating Member State. The Member States in which the clinical investigation is to be conducted shall, within six days of submission of the application, agree on one of them taking the role of the coordinating Member State. If they do not agree on a coordinating Member State, the coordinating Member State proposed by the sponsor shall assume that role.
3. Under the direction of the coordinating Member State referred to in paragraph 2, the Member States concerned shall coordinate their assessment of the application, in particular of the documentation referred to in Chapter II of Annex XV.
However, the completeness of the documentation referred to in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV shall be assessed separately by each Member State concerned in accordance with Article 70(1) to (5).
4. With regard to documentation other than that referred to in the second subparagraph of paragraph 3, the coordinating Member State shall:
(a)
within six days of receipt of the single application, notify the sponsor that it is the coordinating Member State (‘notification date’);
(b)
for the purpose of the validation of the application, take into account any considerations submitted within seven days of the notification date by any Member State concerned;
(c)
within 10 days of the notification date, assess whether the clinical investigation falls within the scope of this Regulation and whether the application is complete, and shall notify the sponsor accordingly.Article 70(1) and (3) to (5) shall apply to the coordinating Member State in relation to that assessment;
(d)
establish the results of its assessment in a draft assessment report to be transmitted within 26 days of the validation date to the Member States concerned. By day 38 after the validation date, the other Member States concerned shall transmit their comments and proposals on the draft assessment report and the underlying application to the coordinating Member State which shall take due account of those comments and proposals in its finalisation of the final assessment report, to be transmitted within 45 days of the validation date to the sponsor and the other Member States concerned.
The final assessment report shall be taken into account by all Member States concerned when deciding on the sponsor’s application in accordance with Article 70(7).
5. As regards the assessment of the documentation referred to in the second subparagraph of paragraph 3, each Member State concerned may request, on a single occasion, additional information from the sponsor. The sponsor shall submit the requested additional information within the period set by the Member State concerned, which shall not exceed 12 days from the receipt of the request. The expiry of the last deadline pursuant to point (d) of paragraph 4 shall be suspended from the date of the request until such time as the additional information has been received.
6. For class IIb and class III devices, the coordinating Member State may also extend the periods referred to in paragraph 4 by a further 50 days, for the purpose of consulting with experts.
7. The Commission may, by means of implementing acts, further specify the procedures and timescales for coordinated assessments to be taken into account by Member States concerned when deciding on the sponsor’s application. Such implementing acts may also set out the procedures and timescales for coordinated assessment in the case of substantial modifications pursuant to paragraph 12 of this Article, in the case of reporting of adverse events pursuant to Article 80(4) and in the case of clinical investigations of combination products between medical devices and medicinal products, where the latter are under a concurrent coordinated assessment of a clinical trial under Regulation (EU) No 536/2014. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3).
8. Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the conduct of the clinical investigation is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of all Member States concerned.
Notwithstanding the first subparagraph, a Member State concerned may only disagree with the conclusion of the coordinating Member State concerning the area of coordinated assessment on the following grounds:
(a)
when it considers that participation in the clinical investigation would lead to a subject receiving treatment inferior to that received in normal clinical practice in that Member State concerned;
(b)
infringement of national law; or
(c)
considerations as regards subject safety and data reliability and robustness submitted under point (b) of paragraph 4.
Where one of the Member States concerned disagrees with the conclusion on the basis of the second subparagraph of this paragraph, it shall communicate its disagreement, together with a detailed justification, through the electronic system referred to in Article 73, to the Commission, to all other Member States concerned and to the sponsor.
9. Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the clinical investigation is not acceptable, that conclusion shall be deemed to be the conclusion of all Member States concerned.
10. A Member State concerned shall refuse to authorise a clinical investigation if it disagrees with the conclusion of the coordinating Member State as regards any of the grounds referred to in the second subparagraph of paragraph 8, or if it finds, on duly justified grounds, that the aspects addressed in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV are not complied with, or where an ethics committee has issued a negative opinion in relation to that clinical investigation, which is valid, in accordance with national law, for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal.
11. Each Member State concerned shall notify the sponsor through the electronic system referred to in Article 73 as to whether the clinical investigation is authorised, whether it is authorised subject to conditions, or whether authorisation has been refused. Notification shall be done by way of one single decision within five days of the transmission, pursuant to point (d) of paragraph 4, by the coordinating Member State of the final assessment report. Where an authorisation of a clinical investigation is subject to conditions, those conditions may only be such that, by their nature, they cannot be fulfilled at the time of that authorisation.
12. Any substantial modifications as referred to in Article 75 shall be notified to the Member States concerned by means of the electronic system referred to in Article 73. Any assessment as to whether there are grounds for disagreement as referred to in the second subparagraph of paragraph 8 of this Article shall be carried out under the direction of the coordinating Member State, except for substantial modifications concerning Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV, which shall be assessed separately by each Member State concerned.
13. The Commission shall provide administrative support to the coordinating Member State in the accomplishment of its tasks under this Chapter.
14. The procedure set out in this Article shall, until 27 May 2027, be applied only by those of the Member States in which the clinical investigation is to be conducted which have agreed to apply it. After 27 May 2027, all Member States shall be required to apply that procedure.
Information from the sponsor at the end of a clinical investigation or in the event of a temporary halt or early termination
1. If the sponsor has temporarily halted a clinical investigation or has terminated a clinical investigation early, it shall inform within 15 days the Member State in which that clinical investigation has been temporarily halted or terminated early, through the electronic system referred to in Article 73, of the temporary halt or early termination, providing a justification. In the event that the sponsor has temporarily halted or terminated early the clinical investigation on safety grounds, it shall inform all Member States in which that clinical investigation is being conducted thereof within 24 hours.
2. The end of a clinical investigation shall be deemed to coincide with the last visit of the last subject unless another point in time for such end is set out in the clinical investigation plan.
3. The sponsor shall notify each Member State in which a clinical investigation was being conducted of the end of that clinical investigation in that Member State. That notification shall be made within 15 days of the end of the clinical investigation in relation to that Member State.
4. If an investigation is conducted in more than one Member State, the sponsor shall notify all Member States in which that clinical investigation was conducted of the end of the clinical investigation in all Member States. That notification shall be made within 15 days of that end of the clinical investigation.
5. Irrespective of the outcome of the clinical investigation, within one year of the end of the clinical investigation or within three months of the early termination or temporary halt, the sponsor shall submit to the Member States in which a clinical investigation was conducted a clinical investigation report as referred to in Section 2.8 of Chapter I and Section 7 of Chapter III of Annex XV.
The clinical investigation report shall be accompanied by a summary presented in terms that are easily understandable to the intended user. Both the report and summary shall be submitted by the sponsor by means of the electronic system referred to in Article 73.
Where, for scientific reasons, it is not possible to submit the clinical investigation report within one year of the end of the investigation, it shall be submitted as soon as it is available. In such case, the clinical investigation plan referred to in Section 3 of Chapter II of Annex XV shall specify when the results of the clinical investigation are going to be available, together with a justification.
6. The Commission shall issue guidelines regarding the content and structure of the summary of the clinical investigation report.
In addition, the Commission may issue guidelines for the formatting and sharing of raw data, for cases where the sponsor decides to share raw data on a voluntary basis. Those guidelines may take as a basis and adapt, where possible, existing guidelines for sharing of raw data in the field of clinical investigations.
7. The summary and the clinical investigation report referred to in paragraph 5 of this Article shall become publicly accessible through the electronic system referred to in Article 73, at the latest when the device is registered in accordance with Article 29 and before it is placed on the market. In cases of early termination or temporary halt, the summary and the report shall become publicly accessible immediately after submission.
If the device is not registered in accordance with Article 29 within one year of the summary and the report having been entered into the electronic system pursuant to paragraph 5 of this Article, they shall become publicly accessible at that point in time.
Corrective measures to be taken by Member States and information exchange between Member States
1. Where a Member State in which a clinical investigation is being or is to be conducted has grounds for considering that the requirements set out in this Regulation are not met, it may take at least any of the following measures on its territory:
(a)
revoke the authorisation for the clinical investigation;
(b)
suspend or terminate the clinical investigation;
(c)
require the sponsor to modify any aspect of the clinical investigation.
2. Before the Member State concerned takes any of the measures referred to in paragraph 1 it shall, except where immediate action is required, ask the sponsor or the investigator or both for their opinion. That opinion shall be delivered within seven days.
3. Where a Member State has taken a measure referred to in paragraph 1 of this Article or has refused a clinical investigation, or has been notified by the sponsor of the early termination of a clinical investigation on safety grounds, that Member State shall communicate the corresponding decision and the grounds therefor to all Member States and the Commission by means of the electronic system referred to in Article 73.
4. Where an application is withdrawn by the sponsor prior to a decision by a Member State, that information shall be made available through the electronic system referred to in Article 73 to all Member States and the Commission.
Substantial modifications to clinical investigations
1. If a sponsor intends to introduce modifications to a clinical investigation that are likely to have a substantial impact on the safety, health or rights of the subjects or on the robustness or reliability of the clinical data generated by the investigation, it shall notify, within one week, by means of the electronic system referred to in Article 73 the Member State(s) in which the clinical investigation is being or is to be conducted of the reasons for and the nature of those modifications. The sponsor shall include an updated version of the relevant documentation referred to in Chapter II of Annex XV as part of the notification. Changes to the relevant documentation shall be clearly identifiable.
2. The Member State shall assess any substantial modification to the clinical investigation in accordance with the procedure laid down in Article 71.
3. The sponsor may implement the modifications referred to in paragraph 1 at the earliest 38 days after the notification referred to in that paragraph, unless:
(a)
the Member State in which the clinical investigation is being or is tobe conducted has notified the sponsor of its refusal based on the grounds referred to in Article 71(4) or on considerations of public health, subject and user safety or health, of public policy, or
(b)
an ethics committee in that Member State has issued a negative opinion in relation to the substantial modification to the clinical investigation, which, in accordance with national law, is valid for that entire Member State.
4. The Member State(s) concerned may extend the period referred to in paragraph 3 by a further seven days, for the purpose of consulting with experts.
Clinical investigations regarding devices bearing the CE marking
1. Where a clinical investigation is to be conducted to further assess, within the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), (‘PMCF investigation’), and where the investigation would involve submitting subjects to procedures additional to those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome, the sponsor shall notify the Member States concerned at least 30 days prior to its commencement by means of the electronic system referred to in Article 73. The sponsor shall include the documentation referred to in Chapter II of Annex XV as part of the notification. Points (b) to (k) and (m) of Article 62(4), Article 75, Article 76, Article 77, Article 80(5) and the relevant provisions of Annex XV shall apply to PMCF investigations.
2. Where a clinical investigation is to be conducted to assess, outside the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), Articles 62 to 81 shall apply.
1. The Commission shall, in collaboration with the Member States, set up, manage and maintain an electronic system:
(a)
to create the single identification numbers for clinical investigations referred to in Article 70(1);
(b)
to be used as an entry point for the submission of all applications ornotifications for clinical investigations referred to in Articles 70, 74, 75 and 78 and for all other submission of data, or processing of data in this context;
(c)
for the exchange of information relating to clinical investigations inaccordance with this Regulation between the Member States and between them and the Commission including the exchange of information referred to in Articles 70 and 76;
(d)
for information to be provided by the sponsor in accordance with Article 77, including the clinical investigation report and its summary as required in paragraph 5 of that Article;
(e)
for reporting on serious adverse events and device deficiencies and related updates referred to in Article 80.
2. When setting up the electronic system referred in paragraph 1 of this Article, the Commission shall ensure that it is interoperable with the EU database for clinical trials on medicinal products for human use set up in accordance with Article 81 of Regulation (EU) No 536/2014 of the European Parliament and of the Council (1) as concerns combined clinical investigations of devices with a clinical trial under that Regulation.
3. The information referred to in point (c) of paragraph 1 shall only be accessible to the Member States and the Commission. The information referred to in the other points of that paragraph shall be accessible to the public, unless, for all or parts of that information, confidentiality of the information is justified on any of the following grounds:
(a)
protection of personal data in accordance with Regulation (EC) No 45/2001;
(b)
protection of commercially confidential information, especially in the investigators brochure, in particular through taking into account the status of the conformity assessment for the device, unless there is an overriding public interest in disclosure;
(c)
effective supervision of the conduct of the clinical investigation by the Member State(s) concerned.
4. No personal data of subjects shall be publicly available.
5. The user interface of the electronic system referred to in paragraph 1 shall be available in all official languages of the Union.
(1) Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (OJ L 158, 27.5.2014, p. 1).
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