Guidance on application for the authorisation for clinical investigation of medical devices

Updated 05 July 2018

Introduction
Application
Clinical investigation plan
Investigator's Brochure
Contraception
Dispensing/sale
Labelling and instructions for use
Information to patients/subjects
Authorisation
Amendments to the clinical investigation
Completion of the clinical investigation
Managment of adverse events
Final report
The Danish Medicines Agency's handling of the application
Inspections
Conduct and reporting of clinical investigation
Legislation
Contact

1. Introduction

Clinical investigations of medical devices are any investigations on humans which serve the purpose of verifying or testing the safety and/or performance of a medical device. The following clinical investigations require authorisation by the Danish Medicines Agency:

non CE-marked devices
CE-marked devices, if the objective of the investigation is application of the device for a new purpose for which the device is not CE-marked
in vitro diagnostic devices, if the device is intended to come in direct or indirect contact with the human body.

The clinical investigation may be initiated when the Danish Medicines Agency and the research ethics committee have granted authorisation. The intention is to ensure that only investigations with acceptable risks and benefits in relation to patient safety are initiated.

Note: Clinical investigation of CE-marked devices utilised for their intended purpose do not require authorisation by the Danish Medicines Agency.

Requirements for clinical investigations are described in the relevant standard published by Danish Standards:

EN ISO 14155:2012. Clinical investigation of medical devices for human subjects – Good clinical practice

Harmonised standards specify the method of how to meet the legal requirements in the relevant area. If non-harmonised standards are used, it should be considered carefully whether the use of the standard meets the requirements of the directive. If standards are not applied, it must be demonstrated how the legal requirements are met.

2. Application

2.1 The application must include the following documents:

The Danish Medicines Agency's application form for clinical investigations
a cover letter, including a list of all appendices and a description of any special conditions that the Danish Medicines Agency should pay attention to
a clinical investigation plan
Investigator's Brochure (IB)
subject information and informed consent form
authorisation sheet, allowing the Danish Medicines Agency to access the subject’s record
statement certifying that the device complies with the essential requirements (including reference to the relevant medical devices directive) apart from the aspects covered by the investigation, and that with regard to these aspects, every precaution has been taken to protect the health and safety of the subjects
a description of the specified intended use of the CE-marked device, a copy of the device’s declaration of conformity as well as certificates from the notified body, if relevant
a copy of the approval from a research ethics committee, if available
picture of the device or a specimen.

The executive order on applications for the authorisation for clinical investigations of medical devices provides a list of the information and documentation to be included in the application. If a limited number of items in the executive order are considered irrelevant to a specific clinical investigation, a list of these items as well as the justification for the omissions must be provided, for example in the covering letter.

Please note that the assessment of the application will not be initiated until the application contains the adequate information

Please send the application to:

Danish Medicines Agency
Medical Devices, Pharmacovigilance & Medical Devices
Axel Heides Gade 1
2300 Copenhagen S
Denmark

One copy of all documents with relevant signatures should be submitted.

The Danish Medicines Agency prefers to receive clinical investigation applications on CD-ROM or online via Eudralink.

The requested file format is as follows:

Documents should be included in one PDF file with bookmarks for each document.
The maximum file size is 40 MB. If the application is bigger, the clinical investigation plan/investigator's brochure should be included in a separate file.

CD-ROM

If the application is submitted on a CD-ROM, a signed cover letter must be included in paper form and as a PDF file on the CD-ROM.

Eudralink

If you choose to send the documentation via Eudralink, please send it to Send an email without a password. In the subject field, please write the name of the sponsor, the name of the investigational device and the subject matter. Eudralink is the European Medicines Agency's (EMA) secure file transfer system. You can register as a Eudralink user here: https://eudralink.ema.europa.eu/. Click Support to be registered in the Eudralink system and ask for a Eudralink account via the appearing e-mail. You will receive a form that you should fill in and submit. Registration in the system is usually established within a few hours.

E-mail

If you submit more information about the clinical investigation by e-mail, please note that the size of e-mails that you can send to the Danish Medicines Agency is limited.

E-mails larger than 25 MB will not be received by the Danish Medicines Agency. Please note that the sender will not receive notification that the e-mail was not received.

2.2 Fees

The Danish Medicines Agency collects a fee to cover the expenses in connection with the handling of applications for authorisation for clinical investigations of medical devices according to the executive order on fees for medical devices.

The fee applies to all investigations covered by the obligation to apply for authorisation and the Danish Medicines Agency has no statutory authority to grant exemption from the fee.

The fee must be paid to the Danish Medicines Agency after receipt of the invoice.

When submitting amendments to investigation plans/amendments to protocols not yet authorised, no additional fees are to be paid to the Danish Medicines Agency. If this material is submitted while the application is being assessed, this may, depending on the nature of the amendment, take longer for the Danish Medicines Agency to reply to the application.

2.3 Language

The Danish Medicines Agency accepts applications in Danish and English.

2.4 Sponsor

The application must be submitted by the sponsor. The sponsor is the person, institution or company taking responsibility for the initiation and completion of a clinical investigation. The sponsor is usually the manufacturer of the device. The sponsor may delegate tasks, but the ultimate responsibility for the investigation rests with the sponsor. Documentation must be provided for any delegated tasks.

Manufacturers of medical devices available for clinical investigations must meet the requirements laid down in the relevant executive orders on medical devices, including the specific requirements for devices intended for clinical investigation.

Sponsors headquartered outside the EU who wish to initiate clinical investigations in Denmark must have a representative in the EU, whom the Danish Medicines Agency can contact to ensure compliance with the requirements of the relevant executive order on medical devices.

2.5 Application for a multi-centre investigation

For investigations being conducted at more than one centre in Denmark, the sponsor should submit only one full application, including a list of each of the participating investigation centres.

3. Clinical investigation plan

The clinical investigation plan (CIP) is a working document for the sponsor, investigators and monitors. Any information relevant for the completion of the clinical investigation must appear from this document. Generally, the following information must be provided:

general administrative information
information about the medical device under investigation
the objective of the investigation
the design of the investigation
inclusion/exclusion criteria
statistical justification and methods for data analysis of the results
handling of adverse events
unscheduled termination of the investigation
ethical considerations
quality control and quality assurance
publication policy.

The executive order on applications for the authorisation for clinical investigations of medical devices (in Danish) provides a list of the information to be included in the clinical investigation plan. If the applicant assesses that certain items in the executive order are not relevant, a justifiation must be provided.

During the conduct of the clinical investigation, the Case Report Form (CRF) provides the practical means to comply with the clinical investigation plan. The CRF should at all times reflect the CIP and information that is not reflected in the CIP must not be included in the CRF.

Non-compliance with the clinical investigation plan

A procedure for preauthorisations of non-compliance with the clinical investigation plan (waivers) is generally not accepted by the Danish Medicines Agency.

4. Investigator's Brochure

The Investigator’s Brochure shall contain:

A summary of the literature and an evaluation supporting the rationale for the intended use of the device and the design of the clinical investigation.
A general description of the device and its components.
A description of the mechanism of action of the device.
Labelling and Instructions for Use, including possible risks, contra-indications and warnings.
A description of the intended clinical performance.
A description of the materials used in the device.
A summary and evaluation of the in vitro, ex vivo and in vivo data, relevant to the device, including pre-clinical data such as biological studies, non-clinical laboratory studies and animal studies.
A summary of relevant previous clinical experience with the device and with other devices with similar features, including details of how long the device has been on the marketplace and an overview of safety and/or performance related complaints.
Results of the risk analysis and risk assessment.

A list of International standards, complied with in full or in part, including details regarding the extent to which the devices are in compliance.

5. Contraception

It must be clearly stated in the CIP, or in an amendment, that it is ensured that fertile women are not pregnant when included in the investigation (negative pregnancy test at the inclusion) and that safe contraception is used during the entire investigation.

The Danish Medicines Agency acknowledges the following contraceptive products as safe in connection with clinical investigations:

intrauterine device
hormonal contraceptives:
- contraceptive pills
- implants
- transdermal patches
- ovaginal ring
- injections with prolonged release

In certain cases it is accepted to include subjects having a sterilised permanent partner or subjects using double barrier contraceptive methods. However, this should be explicitly justified in special circumstances arising from the study design, the device and/or patient population. Double barrier methods of contraception means a condom combined with a diaphragm.

Sterilised or infertile subjects are exempt from the requirement to use contraception. To be considered sterilised or infertile, subjects must generally have undergone surgical sterilisation (vasectomy/bilateral tubectomy, hysterectomy and bilateral ovariectomy) or be postmenopausal defined as 12 months or more with no menses prior to enrolment.

For some individuals or special populations, there may be arguments against using the above-mentioned methods of contraception. Examples include seriously ill, hospitalised patients or fertile children who are not sexually active

6. Dispensing/Sale

Devices under investigation may only be made available when the authorisation for clinical investigation from the Danish Medicines Agency has been granted.

7. Labelling and instructions for use

All relevant information must appear from the labelling and instructions for use of devices under clinical investigation. The executive orders on medical devices lay down the labelling requirements and the requirements for the instructions for use which also apply to medical devices under clinical investigation (cf. the essential requirements of the executive order on medical devices, appendix 1).

Note: “udelukkende til klinisk afprøvning” (the Danish text for “exclusively for clinical investigations”) must be stated on the labelling and relevant instructions for use of the device under investigation.

8. Information to patients/subjects

8.1 Subject information and informed consent

Regulation on how to inform and obtain consent from subjects participating in clinical investigations appears from the executive order on information and consent on involving trial subjects in biomedical research projects. Among other things, this stipulates the contents of the written and verbal information and how to obtain consent. Furthermore, Guidelines on notification, reporting requirements etc.( health scientific research projects) are available at the website of The National Committee on Health Research Ethics

8.2 Letter of authority

As part of its control with clinical investigations, the Danish Medicines Agency must have access to information about subjects' health and personal circumstances. This access is given by way of a letter of authority signed by the subject.

The letter of authority is an independent document and should clearly appear exactly as a power of attorney, and it should be precisely formulated so as to avoid any doubt about what it covers

the document is a letter of authority (title)
who is granting the letter of authority (the subject)
to whom it is granted (Danish Medicines Agency and other authorities, if any)
what the letter of authority is intended for (access to the patient records)
for what purpose (inspection)
what information
for which period the letter of authority is valid.

A condition for granting authorisation for the conduct of a clinical investigation is that a letter of authority is obtained, granting the Danish Medicines Agency access to this information.

If representatives from foreign authorities are to monitor the investigation, this must appear from the letter of authority.

The written subject information and the form for obtaining the letter of authority must be enclosed with the application to ensure that the above control can be conducted. The assessment of the subject information and consent is carried out by the system of research ethics committees.

9. Authorisation

The investigation may be initiated when the Danish Medicines Agency has granted an authorisation and the system of research ethics committees has approved the investigation.

10. Amendments to the clinical investigation

The list of amendments shows examples of amendments considered to be significant and requiring authorisation from the Danish Medicines Agency as well as amendments that should be notified to the Danish Medicines Agency.

10.1 Significant amendments

The sponsor must apply for authorisation to implement amendments to the clinical investigation if the amendments are significant. Amendments are considered to be significant if they may impact on:

the safety of the subjects
the interpretation of the scientific documentation that serves as the foundation of the investigation
the conduct or management of the investigation, including the introduction of a new coordinating investigator, inclusion of a new Danish centre or new Danish principal investigators
the quality or safety of the medical device under investigation or
other significant aspects.

The application for the authorisation to make amendments must contain an application form for authorisation to make amendments signed by the sponsor and a list of the amendments with a thorough rationale for the amendments. The amended text in the submitted information must be clearly indicated, for example by a different colour.

Amendments may only be implemented once the Danish Medicines Agency has granted authorisation.

The associated fee must be paid to the Danish Medicines Agency after receipt of the invoice.

Major amendments (e.g. amendment of the design of implants) may cause the submitted material to be regarded as a new investigation plan, i.e. an application for a new investigation. In this case, the Danish Medicines Agency will inform the sponsor accordingly.

If the sponsor or investigator becomes aware of circumstances, which might entail a risk to subjects' safety, the sponsor or investigator must immediately undertake the arrangements necessary to protect the subjects. The sponsor must immediately notify the Danish Medicines Agency of these new circumstances, the arrangements made and state these arrangements as an amendment to the investigation.

11. Completion of the clinical investigation

The criteria for the completion of the investigation must be provided in the investigation plan. Usually, this is the last visit of the last patient.

11.1 Completion of the investigation according to plan

No later than 90 days after completion of the investigation, the Danish Medicines Agency must be informed that the investigation has been completed. The final report must be submitted to the Danish Medicines Agency as soon as possible thereafter, and no later than one year after the completion of the investigation. The final report must contain a critical evaluation of all the data collected during the clinical investigation.

Information about completion of the investigation should be submitted using the form notification of completion of the clinical investigation of medical devices.

11.2 Premature termination of the investigation

If an investigation is terminated prematurely, the Danish Medicines Agency must be informed no later than 15 days after termination. The final report must be submitted to the Danish Medicines Agency as soon as possible thereafter. The final report must contain a critical evaluation of all the data collected during the clinical investigation.

Information about completion of the investigation should be submitted using the form notification of completion of the clinical investigation of medical devices

11.3 The Danish Medicines Agency terminates or prohibits an investigation

If the Danish Medicines Agency during the investigation has reasons to believe that the investigation is not conducted according to the application or the authorisation or if any other circumstances give rise to doubt about the safety and the scientific aspects of the investigation, the Danish Medicines Agency is entitled to demand that the investigation be amended, temporarily suspended or prohibited.

Before the Danish Medicines Agency makes a final decision, the sponsor and/or principal/coordinating investigator will be requested to provide a statement within 7 days.

The Danish Medicines Agency may refrain from obtaining this statement if it is assessed that postponing the decision may entail a safety risk to the subjects.

If deciding to suspend or prohibit an investigation, the Danish Medicines Agency immediately announces its decision and grounds to the affected research ethics committee, the European Commission and the competent authority in the other EU/EEA countries

12. Management of adverse events

In its decisions, the Danish Medicines Agency stipulates conditions concerning the reporting of serious adverse events. These conditions correspond to the guidance provided in the EU Commission guidelines on reporting of adverse events ”Guidelines on medical devices. Clinical investigations: Serious adverse event reporting” MEDDEV 2.7/3.

12.1 Serious adverse events during investigations of medical devices

According to the terms of the authorisation, the sponsor must inform the Danish Medicines Agency of all serious adverse events that occur during the investigation. This also applies to events that have not been categorised as device-related.

Serious adverse events

According to the EU Commission guidelines, a serious adverse event is an adverse event that lead to:

death or
a serious deterioration in health that
- resulted in life-threatening illness or injury or
- resulted in permanent impairment of body structure or body function or
- required hospitalisation or prolongation of existing hospitalisation or
- resulted in medical or surgical treatment to prevent the above or
lead to foetal death, congenital anomaly or birth defect or any other negative effect on the foetus.

Serious adverse events – near-incidents

According to the EU Commission guidelines, serious adverse events also include situations in which a device deficiency might have led to the incidents mentioned under 1-3, if suitable action had not been taken or if circumstances had been less fortunate. The Danish Medicines Agency classify these incidents as near-incidents.

Serious adverse events – malpractice

In addition, a serious adverse event can be an incident caused by imprecise or incomplete results from diagnostic equipment leading to incorrect diagnosis, delayed diagnosis or delayed or incorrect treatment and then the above-mentioned incidents will occur.

The sponsor must ensure that a careful evaluation of adverse events and near-incidents is performed, with a view to determining, whether the event is related to the medical device or the investigation. The notification must be accompanied by such evaluation made by the sponsor.

The notification should be submitted using the Danish Medicines Agency's notification form for serious adverse events or the EU Commission's SAE reporting form. The notification should be emailed to Medical Devices at: Send an email

The report must be accompanied by comments on any consequences for the investigation.

Serious adverse events must be reported to the competent authority in all the EU member states in which the investigation is being conducted. The report must be made according to the national guidelines. For more information, please contact the competent authority in each country.

All adverse events and near-incidents occurring during the investigation must be mentioned in the final report. This includes adverse events that have not been categorised as serious.

Deadlines for reporting serious adverse events

The sponsor must ensure that all serious adverse events, including near-incidents, are registered and reported to the Danish Medicines Agency immediately and no later than 7 days after the sponsor became aware of the incident.

However, a serious adverse event which indicates an imminent risk of death, serious injury, or serious illness and which requires prompt remedial action for other patients/subjects, users or other persons must be reported no later than 2 days after the sponsor became aware of the event.

12.2 Annual report and list of serious adverse events and near-incidents

Once a year throughout the duration of the clinical investigation, the sponsor must submit a report on the safety of the subjects to the Danish Medicines Agency. As a minimum, the annual report must contain the following information:

a list of all serious adverse events and near-incidents (in Denmark as well as in the rest of the world) occurred during the investigation
an evaluation of each serious adverse event
an assessment of the risks/benefits of the device under investigation
a conclusion on the safety of the subjects.

13. Final report

The sponsor must inform the Danish Medicines Agency that the investigation has been completed, no later than 90 days after completion of the investigation. As soon as possible thereafter, and no later than one year after the completion of the investigation, the sponsor must submit the final report to the Danish Medicines Agency.

The final report must contain a critical evaluation of all the data collected during the clinical investigation.

14. The Danish Medicines Agency's handling of the application

The Danish Medicines Agency will send a letter within 14 days confirming receipt of the application and stating whether the application is properly completed. For an application to be properly completed, it must contain all the information and documentation stated in the executive order on application for the authorisation for clinical investigations of medical devices. For an application to be considered properly completed, the documents must contain sufficient information, including the final results of preclinical testing.

If the application is considered properly completed, the Danish Medicines Agency's review time of 60 days will start, counting from the date of receipt.
If the application is not considered properly completed, the Danish Medicines Agency will inform the applicant. The review time will not start until the Danish Medicines Agency has received the missing information/documents.

If any shortcomings are found during the review of the application, the Danish Medicines Agency will request the missing information with a deadline for submission.

It is important that the deadline is met, as the 60 days review time cannot be suspended. If the requested additional information is not received by the Danish Medicines Agency, a decision will be made based on the information and documentation available at the time.

The result of the review process by the Danish Medicines Agency may be:

authorisation
authorisation with conditions
authorisation with conditions, requires subsequent approval by the Danish Medicines Agency that the conditions have been met
non-approval

If the Danish Medicines Agency estimates that the application may not be approved, a letter of objection will be sent to the sponsor. Subsequently, the applicant has one opportunity to respond to the letter of objection, e.g. by submitting additional information. If the application is not amended according to the objection and within the stated deadline, the application will be rejected (non-approval).

The Danish Medicines Agency will communicate all non-approvals, including the grounds for objection, to the European Commission and the competent authorities in the other EEA countries.

14.1 Other authorities

14.1.1 National Committee on Health Research Ethichs

According to the act on a system of research ethics committees and the Processing of Biomedical Research Projects, one of the regional research ethics committees must approve clinical investigations covered by the act on medical devices.

Regarding applications for authorisation for clinical investigations of medical devices in humans, the Danish Medicines Agency notifies the relevant research ethics committee of its final decision.

More information on applications to the system of research ethics committees is available at the website of the National Committee on Health Research Ethics. Here you can find links to the system of research ethics committees' electronic application form and the regional research ethics committees.

The Danish Medicines Agency’s evaluation of an application may take place at the same time as the evaluation by the system of research ethics committees. For the sake of the review process, it is important that the contents of the clinical investigation plan, which forms the basis for the evaluation in the two systems, are identical.

14.1.2 DANISH DATA PROTECTION AGENCY

After implementation of the General Data Protection Regulation, clinical investigations of medical devices no longer need to be notified to the Danish Data Protection Agency.

Further information in Danish is available at the website of the Danish Data Protection Agency.

Contact the Danish Data Protection Agency at Send an email or call +45 33193200.

14.1.3 NATIONAL INSTITUTE OF RADIATION PROTECTION

Use of medical devices emitting ionising radiation require approval by the Danish National Institute of Radiation Protection, prior to use in a clinical investigation. For more information about notification and approval, please contact The National Institute of Radiation Protection

15. Inspections

Every year, the Danish Medicines Agency carries out inspections on a random sample basis of clinical investigations for which authorisation has been granted in Denmark. Inspections may take place at the premises of the companies managing a clinical investigation (the sponsor) and the investigators carrying out the investigations. In addition, inspections can be made at other parties participating in the investigations, e.g. CRO, laboratories and the like.

The purpose of the inspections is to check that the clinical investigations of medical devices are carried out in compliance with the authorised CIP, the Danish legislation and the standard for clinical investigation of medical devices. This includes that

all involved parties have the appropriate qualifications to manage their tasks in connection with the investigation
the sponsor maintains a quality system to document that all involved parties comply with their obligations pursuant to the CIP and with other relevant requirements for the investigation
the approved CIP is complied with
valid authorisations have been obtained.

Medical Devices of the Danish Medicines Agency is responsible for reviewing applications for clinical investigations and for issuing authorisations. To ensure that the inspections are impartial, they will not be conducted by an employee of Medical Devices, but by a GCP-inspector, who has experience with conducting inspections of clinical investigations and who has been trained in the legislation and relevant applicable standards for clinical investigations of medical devices.

A clinical investigation will be inspected in accordance with the legal requirements as well as the rules which the sponsor has stated as being applicable for the investigation, e.g. EN ISO 14155:2011. A representative of the Danish Medicines Agency's Medical Devices may participate in the inspection as a technical resource.

After each inspection, an inspection report will be prepared, including a summary of possible non-compliances with applicable regulations.

The Danish Medicines Agency may check all resources related to any clinical investigation of medical devices and can require all information necessary to check these activities. As part of the inspection, the representatives of the Danish Medicines Agency have access to patient records, etc., provided that the subject, his or her relatives or guardian has consented to or authorised this. Moreover, the clinical investigation plan must include information that the investigator gives the representatives of the Danish Medicines Agency direct access to source data/documents, including patient records, during an inspection.

The Danish Medicines Agency makes annual planned inspections and will in that connection contact the sponsor and investigator to plan the inspection.

16. Conduct and reporting of clinical investigation

Practical guidance on the conduct and reporting of clinical investigations is available in the standard EN ISO 14155:2011. Clinical investigation of medical devices for human subjects – Good clinical practice, published by Danish Standards.

17. Legislation

Medical devices are regulated by the following act and executive orders in Denmark. These are only available in Danish. An overview is listed below:

Act:

Act no. 1046 of 17 December 2002 on medical devices

Executive orders:

18. Contact

If you have any questions, please contact Medical Devices on

Telephone: +45 4488 9595

Monday-Friday 9.30-15.00

Mail: Send an email

Note: E-mails larger than 25 MB will not be received by the Danish Medicines Agency. Please note that the sender will not receive notification that the e-mail was not received.