Clinical studies of medical devices:

Frequently asked questions (FAQ)

 

 

1. Regarding clinical evaluation, how should compliance of a medical device with the essential requirements be demonstrated?

In general, the demonstration of compliance with the essential requirements must include a clinical evaluation based on clinical data assessment, as set out in Decree-Law No. 145/2009 of June 17 (part I of annex XVI) and Law No. 21/2014 of April 16.

 

2. What is clinical data?

Clinical data is the safety and/or performance information that is generated from the use of a device. Clinical data are sourced from clinical investigation(s) of the device concerned; clinical investigation(s) or other studies reported in the scientific literature, of a similar device for which equivalence to the device in question can be demonstrated; published and/or unpublished reports on other clinical experience of either the device in question or a similar device for which equivalence to the device in question can be demonstrated.

 

3. What is the legislation applicable to clinical investigation of medical devices?

The rights and duties of investigators, sponsors and the National Competent Authority are set out in the Directives 93/42/EEC of June 14 and 90/385/EEC of June 20, in their current versions, which have been transposed to the national legal system by the Decree-Law No. 145/2009 of June 17.
At the national level, Law No. 21/2014 of April 16 regulates clinical research and lays down the obligations relating to clinical studies of medical devices and the system by which the sponsor submits these studies to the National Competent Authority and to the Competent Ethics Committee (CEC).
INFARMED, I.P., as the National Competent Authority for medical devices, has the role of monitoring the compliance with this legislation.

 

4. Who is responsible for issuing the ethics opinion to carry out clinical studies for medical devices?

For interventional clinical studies of medical devices, the Competent Ethics Committee is the National Ethics Committee for Clinical Research (CEIC), unless it designates a local ethics committee for health (CES) for the purpose.
For other clinical studies of medical devices, the Competent Ethics Committee is the local ethics committee for health based on the investigation site/centre (CES). In the case of the involved study center don't have an ethics committee, the Competent Ethics Committee is the CEIC or, alternatively, other CES designated by CEIC.

 

5. What is a medical device for clinical investigation?

A medical device for clinical investigation is any medical device designed to be used by an investigator in an investigation center in order to be submitted to the studies referred to in Law No. 21/2014 of April 16.

 

6. Who can conduct clinical investigation with medical devices?

The clinical investigation with medical devices should be performed by physicians or technicians with scientific qualifications and appropriate experience, particularly in research and preferably in the area of the proposed research.

 

7. Where can be conducted clinical investigation with medical devices?

The clinical investigation with medical devices should be carried out in health facilities (public and private), laboratories or other entities having the appropriate materials and human resources.

 

8. How to submit an interventional clinical study of medical devices to Infarmed?

The sponsor should submit to Infarmed all interventional clinical studies of medical devices, as established in article 33 of Law No. 21/2014 of April 16.
In this context, the sponsor must request an authorization to carry out the study if devices are class III, implantable or invasive of class IIa or IIb to use for long periods.
For the remaining devices, the sponsor must notify the clinical study to Infarmed.

All clinical studies of medical devices require the opinion of the Competent Ethics Committee (CEC).

 

9. How to submit a clinical study of medical devices to the Competent Ethics Committee (CEC)?

For interventional clinical studies of medical devices, the Competent Ethics Committee (CEC) is the CEIC, unless it designates a local ethics committee for health (CES) for the purpose.
The sponsor must take into account the CEIC submission instructions: Instructions and Administrative Validation.

For non interventional clinical studies of medical devices, the Competent Ethics Committee (CEC) is the local ethics committee for health of each investigation site/centre (CES), so the sponsor must take into account the submission instructions for each study site.

All relevant documentation should be submitted via RNEC, as provided in the "Technical and Functional Specifications", in accordance with article 10 of Ordinance No. 65/2015 of March 5.

 

10. How to submit an application for authorization/notification of an interventional clinical study of medical devices to Infarmed?

Law No. 21/2014 of April 16 defines the creation of the National Database for Clinical Studies (RNEC), which have features regarding the electronic submission of interventional clinical studies of medical devices.

All relevant documentation should be submitted via RNEC, as provided in the "Technical and Functional Specifications", in accordance with article 10 of Ordinance No. 65/2015 of March 5.

 

11. How to submit to the CEIC the documentation for requesting an opinion to conduct an interventional clinical study of medical devices?

All relevant documentation should be submitted via RNEC, as provided in the "Technical and Functional Specifications", in accordance with article 10 of Ordinance No. 65/2015 of March 5.

 

12. What documents must be submitted to Infarmed?

The sponsor of an interventional clinical study of medical devices must submit to the Health Products Directorate of Infarmed, via RNEC, the following documents:

1. Cover letter;
2. The "Form for medical devices in clinical investigation";
3. The "Statment of clinical investigation with medical devices";
4. Clinical investigation plan/protocol;
5. The investigator's brochure;
6. Informed consent;
7. Proof of insurance;
8. Labelling and instructions for use;
9. The opinion of the CEIC - National Ethics Committee for Clinical Research (if available at the time of submission);
10. Up to date CV of the principal investigator of each center;
11. Payment guide and receipt of the fee (or, alternatively, proof of exemption from fee payment, in accordance with the provisions of clause 3 of Ordinance No. 63/2015 of March 5).

In the case of medical devices already bearing the CE marking, but that will be used for a different medical purpose other than that refered to in the relevant conformity assessment procedure, it should also be submitted:

12. Copy of the CE Declaration of conformity;
13. Copy of the labelling;
14. Copy of the instructions for use;
15. Copy of the CE Certificate (if applicable).

In the case of interventional post-market clinical studies of medical devices, the sponsor must submit all the documents above mentioned (except for the "Statment of clinical investigation with medical devices") as well as:

16. Information on relevant data gathered from PMS (post market surveillance plan) and PMCF (post market clinical follow-up).

The sponsor shall keep for a minimum of 5 years for medical devices, and 15 years for implantable medical devices, all the documentation related to the realization and monitoring of the clinical study.

The labelling of medical devices subject to clinical studies should have inscribed the mention "Exclusive for clinical investigation" (as stated on annex I, paragraph 13.5.8 and paragraph 17.2, e) of annex X of Decree-Law No. 145/2009 of June 17).
These devices can only be used within the clinical investigation and under the responsibility of authorized personnel for this same investigation.

 

13. What documents must be submitted to the CEIC?

All information about the necessary documentation for the submission process is available through the following links: Instructions and Administrative Validation.

 

14. What is the "clinical investigation plan/protocol" for clinical studies with medical devices?

Law No. 21/2014 of April 16 defines «clinical investigation plan/protocol» as the document that state(s) the rationale, objectives, design, methodology, monitoring, statistical aspects, the organization and the conduct of a study, as well as the record-keeping, including the various versions and amendments of that document.

 

15. Can medical devices without CE marking be subjected to clinical investigation?

Yes. Although not bearing the CE marking, the devices for clinical investigation can be made available to physicians or other professionals authorized for that purpose, as long as the conditions set out in annexes I, VIII, XV and part I of annex XVI of Decree-Law No. 145/2009 of 17 June, are met. The labelling and the instructions leaflet must be written in Portuguese.

 

16. Interventional clinical studies for medical devices with CE marking must be submitted to Infarmed?

Yes. Law No. 21/2014 of April 16 does not distinguish clinical studies of medical devices with or without CE marking. Thus, all interventional clinical studies of medical devices must be submitted to Infarmed, regardless of the device under study bearing or not the CE marking.

 

17. How, and to whom, serious adverse events occurring in the context of interventional clinical studies of medical devices should be notified?

All serious adverse events (SAE) must be fully recorded and immediately notified to the competent authority - Health Products Directorate of Infarmed - and to all competent authorities of the Member States where the study is being performed. Law No. 21/2014 of April 16, in its article 22, sets the deadlines for such notifications.

For pre-market interventional clinical studies should be used the reporting form template for summary SAE tabulation attached to the guideline MEDDEV 2.7/3 - Clinical investigations: Serious adverse event reporting. The sponsor must also send the annual cumulative safety report, compiling the gathered data and a critical analysis.

For post-market studies the sponsor must notify to the competent authority - Health Products Directorate of INFARMED, I.P. - the annual cumulative safety report, safeguarding that depending on the course of the study other periodicity may be proven as necessary.

All relevant documentation should be submitted via RNEC, as provided in the "Technical and Functional Specifications", in accordance with article 10 of Ordinance No. 65/2015 of March 5.

It should also be noted that, in the case of post-market studies, the manufacturer must guarantee that when a serious adverse event that occur in Portugal regarding which there is a suspect of relationship to the device (i.e. meets the criteria of notification via Vigilance System) is individually notified to the Vigilance Unit of Infarmed using the appropriate European harmonized template as per MEDDEV 2.12/1 rev.8 that can be sent by e-mail to dvps@infarmed.pt .

For more information please follow this link.

 

18. How to notify the CEIC of all serious adverse events?

Notification of serious adverse events must be done in accordance with the instructions mentioned above (FAQ no. 17).

 

19. An authorization to conduct an interventional clinical study of medical devices may be suspended or withdrawn?

An interventional clinical study of medical devices could be suspended or withdrawn after the detection of an anomalous situation, in particular for security reasons of subjects and/or users of the medical device.

 

20. It is required that the sponsor of a clinical investigation with medical devices request an opinion to an ethics committee?

Yes. Conducting a clinical investigation with medical devices in Portugal depends on the issue of a favorable opinion by the competent ethics committee (CEC), according to Law No. 21/2014 of April 16.
For interventional clinical studies of medical devices the competent ethics committee is the National Ethics Committee for Clinical Research (CEIC), which issues an opinion, unless it appoints a local ethics committee for health (CES) for this purpose (article 16, paragraph 2 of Law No. 21/2014 of April 16).
For non-interventional clinical studies of medical devices the competent ethics committee is the local ethics committee for health (CES) of the investiation site/centre or, in the case of the site don't have such a committee, the CEIC or other CES designated.

 

21. Who can suspend or withdraw the authorization to conduct a clinical study of medical devices?

According to Law No. 21/2014 of April 16, Infarmed or the competent ethics committee may suspend or withdraw the authorization to carry out the study if there are objective reasons to consider that the conditions under which the authorization (Infarmed) or opinion (CEIC) were based are no longer met or if there is information that raises doubts about the safety or scientific validity of the clinical study.

 

22. The sponsor of a clinical study of medical devices may be someone other than the manufacturer of the devices (eg.: a hospital, a centre for biomedical research, the investigator, etc.)?

Directives No. 93/42/EEC of June 14, concerning medical devices, and No. 90/385/EEC of June 20, relating to active implantable medical devices, both altered by Directive 2007/47/EC of September 5, establish the legal requirements to clinical investigation with commercial purposes.
However, Law No. 21/2014 of April 16 defines a sponsor as "the individual or collective, the institute or the body responsible for the design, development, management or financing of a clinical study". Thus, the sponsor may be the manufacturer if the study has a commercial purpose, or other entity (including the investigator himself) in studies with non-commercial purposes.

 

23. Interventional clinical studies of medical devices are required to pay fees?

Yes. According to Ordinance No. 63/2015 of March 5, the payment of a fee upon the submission of an interventional clinical study of medical devices is mandatory. Additional information can be found here.

24. Is it also necessary to pay a fee to the competent ethics committee?

For interventional clinical studies of medical devices submitted both to Infarmed and to the CEIC there is only a one fee. Proof of the payment of this fee must be sent via RNEC to the entity to which the study is submitted in the first place.
There is no fee for clinical studies of medical devices submitted to the local ethics committees for health (CES) of the investigation site/centre.

25. In which cases is it possible an exemption from fees?

Ordinance No. 63/2015 of March 5, in its clause 3 provides for the possibility of the Board of Infarmed to grant exemption from the payment of fees regarding the conduct of clinical studies, when the sponsor of studies are non-profit institutions or when dealing with clinical studies of non-commercial nature.

 

26. How to apply for an exemption from fees?

In order to request this exemption the sponsor must, prior to the submission of the clinical study, send an application addressed to the Board of Infarmed, which must attach the statutes of the sponsor' institution. Also, if applicable, a statement signed by the head of the same institution where is clarified that the study in question has no commercial purpose can be submited.
If the request for the exemption from fees was made after the payment, and in the case of a favorable decision by the Board of Infarmed, it should be requested the reimbursement to the Accounting Unit of Infarmed. This request should be supported by documentation.

 

27. Is the refunding of fees possible?

Article 4 of Ordinance No. 63/2015 of March 5 provides that, in the case of a non aproval decision of the clinical study, it should be returned 90% of the paid fees to the sponsor, retaining 10% of this value for administrative costs.

 

28. Regarding the studies which obtained an opinion by the competent ethics committee (CEC) after June 16 of 2014, to whom must be submitted the request for substantial amendment ?

For all substantial amendments, and notifications, regarding clinical studies of medical devices previously approved by CES (studies approved before the entry into force of Law No. 21/2014 of April 16), the competent ethics committee (CEC) is the local ethics committee for health (CES) which approved the study.

 

29. How to send the opinions of the ethics committees at the time of the submission of a study to the CEIC?

As an alternative to sending the opinions, it can be sent a list summarizing the opinions (both favorable and unfavorable) of the ethics committees to which was submitted the application, similar to the list of the competent authorities.

 

30. The submission of an interventional clinical study of medical devices to the CEIC requires the authorization of the managment board of the investigation site?

The authorization of the board may be waived by the existence of the final version, or a draft, of the financial contract, since the submission of this document assumes that there have been negotiations with the centre as well as acceptance by the board for conducting the study.

 

31. Upon submission of an interventional clinical study of medical devices to the CEIC, what is the role of the coordinating investigator?

Regarding the submission of multicentre studies:
The clinical investigation plan/protocol (CIP) should be signed by the sponsor and the coordinating investigator. In his absence, by all principal investigators of the study and the sponsor. The ethical evaluation should be made and signed by the coordinating investigator. In his absence, by one of the principal investigators designated to do so.
The request of substantial amendments to the protocol must always be signed by the sponsor and all principal investigators. Alternatively to the signatures of all principal investigators, it can be sent a statement by the sponsor assuring that all investigators will take notice of the amendments before its implementation.

Regarding the submission of studies in one centre:
The CIP should be signed by the principal investigator.
The ethical evaluation should be made and signed by the principal investigator.

 

32. Is the existence of a "coordinating investigator" mandatory?

No. The existence of a coordinating investigator is not mandatory, even in multicentre studies.

 

33. What is the "Form for notification of medical devices intended for clinical investigation", in the checklist of the CEIC?

This form, to be completed and sent to the CEIC, is the same used for the submission to Infarmed.

 

34. The epidemiological studies with medical devices on oral health/diseases, or the retrospective studies whose purpose is to assess the partial or total prosthetic rehabilitation of patients, require approval by the CEIC?

Clinical studies of medical devices always require a favorable opinion of a competent ethics committee, which will be the CEIC for interventional clinical studies of medical devices.
In the case of non-interventional clinical studies of medical devices, the competent ethics committee is the local ethics committee for health (CES) of the investigation site/centre or, in the case of this centre don't have such a committee, the CEIC or other CES designated.

According to the type of study, the competent ethics committee will be the ethics committee for health of the institution. If the ethics committee of the investigation site is not an ethics committee for health, as set by Law No. 97/95 of May 10, then the study should be evaluated by the CEIC.

 

35. What is the EUDAMED number mentioned in clinical studies of medical devices?

The EUDAMED number is a sequential number generated by the European Database on Medical Devices - EUDAMED - which allows an unique identification of a given pre-market clinical study of a medical device.

 

36. Who issues the EUDAMED number?

The EUDAMED number is issued for a given clinical study of medical devices by the first competent authority to which the study was submitted.

 

37. Is it mandatory to submit the EUDAMED number at the time of submission of a clinical study of medical devices?

Yes. For pre-market clinical studies of medical devices there must be always an EUDAMED number, which must be submitted to Infarmed and the to CEIC upon submission of the study.
If the study only takes place in Portugal, or if Portugal is the first Member State in which the study is submitted, Infarmed will inform the sponsor on the assigned EUDAMED number.
The EUDAMED number does not apply to post-marketing clinical studies.