Procedure 4: Responsibilities and tasks in connection with clinical trials of medical devices

1. Purpose

The purpose of this procedure is to ensure that research projects which, in addition to being subject to the Norwegian Health Research Act, also are subject to the Norwegian legislation on clinical trial of medical devices (and in more detail in the Guidelines on Notification for Clinical Investigation of Medical Devices in Norway) are planned, organized, initiated, conducted, reported, completed and closed out, in a sound manner and in accordance with applicable law, including a sound internal evaluation and determination of which legislation applies, including privacy protection.

Furthermore, the procedure must ensure that necessary agreements, notifications and approvals are in place before the project starts and that these are adhered to throughout the clinical trial period up to reporting and in the event of any publication.

2. Scope

This procedure applies to all research at UiO 

• which is subject to the Health Research Act 
• which is subject to the obligation for approval or obligation for notification ofinvolves testing of medical devices on humans (see 4.8. for the obligation to submit an application) 
• in which UiO and/or UIO employees have the role of Sponsor and/or Principal Investigator 
• which must be conducted in accordance with UiO's quality assurance system for health and medical research

Clinical trials on medical devices that is conducted in collaboration with other institutions (for example university hospitals) or other partners (for example manufacturers of medical devices) may be conducted in accordance with the cooperating party's quality assurance system if this is laid down in an agreement (for example a framework agreement, cooperative agreement or project agreement). The agreement must specify roles and responsibilities, and in particular it must be specified which of the parties has sponsor responsibility pursuant to the legislation.

If it is planned for the UiO to have the responsibility of the sponsor, this must be clarified with the representative of the person responsible for research in connection with an internal presentation of the project (ref Procedure 02 Responsibilities and tasks of the project manager).

3. Responsibility

In accordance with the international quality standard for clinical trial of medical devices: NS-EN ISO 14155 ¡°Clinical trial of medical devices for human subjects¡±, responsibility is divided between the two parties; Sponsor and Investigator (for a definition see Chapter 7 of this procedure). UiO may have one or both roles at the same time in the same trial of a medical device. UiO may also be the manufacturer of a medical device that is in development.

The representative of the institution responsible for research is responsible for a potential clarification of the sponsor¡¯s responsibility to be made in cooperation with the relevant administrative and professional competence for the trial in question.

Sponsor of trials of medical devices  is responsible for:

• ensuring that the project has a qualified Principal Investigator (Project Manager)
• ensuring that the necessary contact is established with the manufacturer of the medical device, or the latter's representative in the EEA
• preparing a project protocol in cooperation with the Principal Investigator or National Coordinating Investigator
• ensuring that trial subjects are insured
• ensuring that applications to the Norwegian Medical Products Agency are prepared where this is required
• documenting that the trial site has satisfactory facilities
• ensuring that a study initiation visit is held
• ensuring that the clinical trial is monitored by a monitor who is independent of the investigator
• receiving from Investigator and classifying reports of adverse events
• reporting to the Norwegian Medical Products Agency any serious device failures and other serious adverse events that may be related to the use of the device
• ensuring that amendments to the protocol are approved by the Norwegian Medical Products Agency before they are implemented
• ensuring that the closing out of the clinical trial is documented.
• regulatory archiving and storage of the Sponsor's project documentation in accordance with UiO's operating procedures
• handling and processing of data
• final report and reports to the Norwegian Medical Products Agency and REK
• ensuring that necessary medical devices are available for the investigation
• ensuring that there is a written agreement with the Coordination Investigator and the Principal Investigators
• signing the project plan (the clinical trial protocol)
• contracts with subcontractors
• follow-up of the project budget in accordance with UiO's operating procedures
• posting in Clinicaltrials.gov if this is required

The Sponsor is also responsible for the monitoring (supervision) of the trial by a qualified person (monitor). This person must be independent of the investigator (the project manager), ie. be employed or have a written agreement with the sponsor specifying the tasks which should be completed in connection with the monitoring. A plan (monitoring plan) should be available for the monitoring (see also section 4.15).

The Principal Investigator (Project Manager) is responsible for:

• preparing a project protocol in cooperation with the Sponsor
• conducting an independent assessment of the soundness of the project, including privacy protection.
• appropriate delegation of tasks within the project team
• ensuring that delegation of tasks to qualified project team members is documented
• submission to the Sponsor's representative, in accordance with the unit's procedures and the procedure for submission in connection with external financing, when relevant
• communication with the Sponsor's (institution responsible for research) representative  in the unit and with UiO¡¯s data handler officer
• registering the project in UiO¡¯s system for a continuous overview, FORSKPRO
• ensuring that approval is obtained from Regional Committee for Medical and Health Research Ethics (REK) before an application is submitted to the Norwegian Medical Products Agency
• notifying the Sikt of the project
• ensuring that the trial subjects give informed consent
• keeping a complete list of subjects
• the daily conduct of the clinical trial
• communication with the REK and Sikt
• overall accountability of medical devices used in the clinical trial
• storage and handling of medical devices
• ensuring that data are obtained and recorded accurately
• regulatory archiving and storage of the Principal Investigator's project documentation in accordance with UiO's operating procedures
• reporting of device failure and adverse events to the Sponsor
• ensuring that the research project is conducted in accordance with approved conditions
• ensuring that amendments to the trial protocol are approved by the Norwegian Medical Products Agency, REK and Sikt before they are implemented
• ensuring that research data are handled and stored in accordance with UiO's procedures
• information to trial subjects in connection with injuries or complications
• final notification and if appropriate reports to REK

National Coordinating Investigator (in multi-centre trials) is responsible for:

• ensuring that applications and any amendment applications are sent to REK
• signing the protocol in multi-centre clinical investigations

4. Description of tasks

4.1. Documentation of Principal Investigator and trial site (Sponsor's responsibility)

Each trial site in a clinical trial of a medical device must have a Principal Investigator. The Principal Investigator's qualifications must be documented by means of a CV. If the principal investigator is not personally a physician or dentist who is qualified to safeguard the trial subjects' health and welfare on a continuous basis, such a person must be appointed and this must be documented as described in point 4.3.

Sponsor's permanent representative must determine whether the trial site fulfils the requirements for implementing the protocol. This assessment must be documented according to Appendix 4.1 Form for documentation of Principal Investigator and trial site. There must be a National Coordinating Investigator in addition for multi-centre trials.

4.2. Clarification of responsibility in cooperative projects (Sponsor's and Principal Investigator's responsibilities)

In clinical trials on medical devices that are cooperation projects with other institutions, research responsibility must be defined, and a written agreement be in place before the project starts. Sponsor (institution responsible for research) and the Principal Investigator (Project Manager) must be named in the agreement. Principal Investigator must have appropriate research qualifications and experience for the project in question. The quality system to be used for the project must be stated.

4.3. Principal Investigator's delegation of tasks (Principal Investigator's responsibility)

Tasks to be carried out in the clinical trial may be delegated by the Principal Investigator to project team members. The individual project team member must have qualifications appropriate to the tasks he/she has been delegated. Delegation of tasks and project members' qualifications must be documented pursuant to Appendix 4.2 Form for Principal Investigator's delegation of tasks

4.4. Insurance

The Norwegian Medical Products Agency must be contacted in each case in order to clarify the matter of insurance.

4.5. Internal submission of the project (Principal Investigator's responsibility)

Before the project is initiated, it must be submitted to the Sponsor's permanent representative at the units, in accordance with the faculty's, institute's or unit's procedures and UiO's procedure for submission in connection with external financing when this is relevant. This submission and the assessment must be documented in accordance with Procedure description 2, Appendix 2.1 Project planning form, and registered on the unit's list of projects. The assessment shall comprise the following points:

• Principal Investigator's qualifications
• Resources
• Consistency with the unit's research strategy
• Review of the Project Manager's independent assessment of soundness, including privacy protection; see point 4.6.
• Need for contact with the manufacturer of the device that is to be investigated
• Requirement for an application to the Norwegian Medical Products Agency

In addition, for clinical trials on medical devices an assessment should be conducted regarding

• Whether cooperating partners are relevant and qualified
• Which institution should possess the role of sponsor

Clinical trials on medical devices should primarily be conducted with the cooperating partner as the sponsor.

If UiO is wanted for the role of sponsor this should be closely assessed and planned in cooperation with UiO¡¯s representative of the research responsible and specific competence in the research field in question, if required. If, in understanding with the represeentative of the responsible for research, it is decided that UiO should possess the role of sponsor, resource should be allocated for use of an external partner (third party provider) for research support. This is necessary to ensure compliance with the obligations of the sponsor to the authorities

The decision that the UiO is to possess the role of the sponsor must be confirmed at the level of dean or similar.
 

4.6. Principal Investigator's assessment of soundness (Principal Investigator's responsibility)

Before the project is submitted to REK and possibly other authorities for advance approval, the Principal Investigator must make an independent assessment of whether ethical, medical, healthcare, scientific, protection of privacy and information security aspects are safeguarded in the project. A similar assessment must be carried out regularly during the course of the project, particularly in connection with plans for amendments.

4.7. Preparation of the trial protocol (Sponsor's and Principal Investigator's responsibility)

The trial protocol with appendices must be prepared in accordance with Appendix 4. 3. Checklist trial protocol. Necessary information and documentation must be obtained from the manufacturer of the medical device. All documents must have version control, i.e. version number and date. In clinical trial of medical devices, there must always be a separate trial protocol that must be signed by the Sponsor and Principal Investigator (in multi-centre trials, by the National Coordinating Investigator).

4.8. Application for advance approval by authorities (Sponsor's and Principal Investigator's responsibility)

Before the trial commences, the necessary approvals must be obtained from REK and the
Norwegian Medical Products Agency. Applications to REK and potentially to the Norwegian Medical Products Agency must be submitted on the same day.

An application to the Norwegian Medical Products Agency must be sent to  medisinsk.utstyr@legemiddelverket.no. For information on the application and the application process for the Norwegian Medical Products Agency, see
https://legemiddelverket.no/medisinsk-utstyr/hvordan-sette-medisinsk-utstyr-pamarkedet/
klinisk-utproving-av-medisinsk-utstyr/kliniske-utprovinger-som-krever-soknad-tillegemiddelverket#2.

For a listing of the attachments to the application, please see
https://legemiddelverket.no/medisinsk-utstyr/hvordan-sette-medisinsk-utstyr-pamarkedet/
klinisk-utproving-av-medisinsk-utstyr/kliniske-utprovinger-som-krever-soknad-tillegemiddelverket#2, section 2.
 

Applications for approval must be complete and have appended a final, signed version of the project protocol and a final, dated version of other documents.  The Principal Investigator is responsible for sending an application to REK, for following this up and for further communication with REK. The Sponsor is responsible for sending an application to the Norwegian Medical Products Agency, for following this up and for further communication with the Norwegian Medical Products Agency.

Obligation to submit application: Approval from REK must always be obtained.

An application to the Norwegian Medical Products Agency is usually not required for medical devices that are CE- marked and which in the trial in question will be used in the same manner as for ordinary clinical use of the equipment. Such trials must still be notified (an approval is not required) if they involve additional procedures which are invasive or which entail additional burdens for the trial participants.

The Sponsor is required to send an application for approval to the Norwegian Medical Products Agency for medical devices that are not CE-marked  and for medical devices which are CE-marked but which in the trial in question will be used in a manner other than the ordinary clinical use of the device. Safety information and risk analyses must be obtained from the manufacturer.

In the case of non-CE-marked devices, the manufacturer is required to sign the application to the Norwegian Medical Products Agency.

4.9 Notification to Sikt

Prior to the initiation of the project, it should be notified to Sikt for an advance assessment of the basis for processing of data and potential data protection impact, ref. UiO¡¯s  Procedures for processing personal data in research.

4.10. Posting in Clinicaltrials.gov (Sponsor's responsibility)

After the project has been approved by REK and the Norwegian Medical Products Agency, the question of whether the project is required to be registered in the international database, Clinicaltrials.gov, must be considered. Such registration may be a precondition for publication at a later date.

4.11. Initiation of clinical trial (Sponsor's responsibility)

Before the clinical trial can start, one or more study initiation meetings must be held for training and information concerning the implementation and schedule for the investigation. All investigators and other project team members must attend such a meeting. The meeting agenda and those attending must be documented in accordance with Appendix 4.4 Form for study initiation meeting. Before the first trial subject is informed and invited to take part in the trial, the following documents are required:

• Signed protocol
• Signed financial agreements
• Final approvals from REK and the Norwegian Medical Products Agency
• Assessment from Sikt

4.12. Information and obtaining of informed consent (PrincipalInvestigator's responsibility)

All subjects must receive information about the research project and be asked to consent to participation in accordance with the REK approval. Information and informed consent forms must be prepared in accordance with REK's templates; see Appendix 4.5 REK's templates for participation information and consent. Consents must be documented by means of the date and signature of the subjects, who must also be given a copy of the signed informed consent form. In the event of amendments to the conduct of the project or the use of data, the question of obtaining a new consent must be considered. A new consent must be obtained if the amendment may be considered to influence the subjects' consent. A new informed consent form must be sent to REK together with the amendment application (ref. point 4.12) and must be approved by REK before it is implemented.

The Investigator must keep a list of persons who are invited to take part in the investigation, persons who consent to take part and persons who are included in the trial in accordance with Procedure description 6, Appendix 6.3 Form for subject identity list and list of subjects.

4.13. Application for approval of planned amendments (Sponsor's and Principal Investigator's responsibility)

In the event of plans to make amendments in accordance with Appendix 4.6, REK's procedure for project amendments with checklist, it is necessary to obtain a new approval from the same authorities who gave advance approval. The amendments must be approved before they can be implemented. It may also be necessary to submit the amendments to the research body's representative if this is a part of the institute's/group's procedures.

A list of the types of changes that require a new consent can be found on REK's website; see Appendix 4.6 REK¡¯s project amendment procedure with checklist

4.14 Notification of changes in the processing of personal data

Changes in the processing of personal data in the course of the project period should be notified to Sikt via the notification form, ref. UiO¡¯s procedures for processing personal data in research.    

4.15 Compliance with trial monitoring requirement (Sponsor's responsibility)

Sponsor's permanent representative must appoint a monitor (for definition, see Chapter 7 of this procedure) to supervise the execution and progress of the clinical trials, with focus on the following areas:

• Protection of the subjects' rights
• Quality of collected data
• Technical equipment that is used in the clinical trial (apart from that being investigated)
• Accountability for the medical device being investigated
• Other documentation that is necessary pursuant to legislation

The monitor must have appropriate scientific and clinical knowledge and suitable training in order to maintain this function. The monitor's qualifications and experience must be documented, for example through a CV.

The scope and frequency of the monitoring is described in a monitoring plan; see Appendix 4.7Template for monitoring plan. The monitoring plan must be completed before the trial starts.

Each monitoring visit must be reported in a monitoring report that is sent to the Sponsor's permanent representative; see Appendix 4.8 Monitoring report form.

The last monitoring visit in connection with the close-out of the trial must be reported by means of Appendix 4.10 Project close-out form.

4.16. Compliance with the source documentation requirements (Principal Investigator's responsibility)

Investigator must create and file source documents for each subject. As a minimum, the source documents must contain documentation of the subject's case history /state of health, documentation of each follow-up visit in the trial, documentation of the duration of exposure to the medical device that is being investigated and printouts from laboratory investigations and any other investigations that generate written results. The registration form that is designed for the trial may form part of the source documentation.

4.17. Compliance with requirements regarding storage of medical devices (Principal Investigator's responsibility)

The Principal Investigator shall ensure that the medical device that is being investigated be kept during the trial in accordance with the manufacturer's specifications. Access to the device must be restricted to project team members who have been delegated these tasks in the investigation; see Appendix 4.2 Form for Principal Investigator's delegation of tasks.

4.18. Packaging and delivery of medical device for clinical trials (Sponsor's responsibility)

The Sponsor shall arrange for delivery to the Investigator of the right quantity according to the trial protocol of medical devices that are packaged and labelled according to the manufacturer's specifications. The device must additionally be labelled FOR KLINISK UTPR?VING

4.19. Accountability for medical devices (Principal Investigator's responsibility)

The Principal Investigator must document the number of medical devices delivered to or procured for the clinical trial site, how many of them are used in the investigation, how many remain after the conclusion of the trial and how the unused devices are handled. This also includes medical devices that are returned by subjects. Used and returned devices must be documented for each subject in accordance with Appendix 4.10 Device accountability form

4.20. Information security (Principal Investigator's responsibility)

The Principal Investigator must establish a subject identity list for persons who have consented to take part in the investigation. The subject identity list contains unambiguous personal identification linked to a serial number / participant number in the investigation; see Procedure description 6, Appendix 6.3 Form for subject identity list and list of subjects. The subject identity list and all other documents that contain the subject's name or other personal information, such as informed consent form and source documentation, must only be kept by the Principal Investigator, with restricted and documented access. On registration forms and any other documents submitted by the Principal Investigator to the Sponsor's permanent representative at UiO, external sponsor or data processor, subjects must only be identified by serial number /participant number in the trial.

4.21. Statistics and data processing (Sponsor's responsibility)

The Sponsor shall arrange for competent statistical expertise as well as systems and equipment for entry, processing and storage of data from the clinical trial.

4.22. Report on adverse events and failures (Principal Investigator's responsibility)

Adverse events and device failures must be documented by the Principal Investigator. The registration form that is prepared as an appendix to the trial protocol is used for this purpose. If the Principal Investigator regards the event as serious, the form for reporting of serious adverse events shall be forwarded to the Sponsor's permanent representative within 48 hours; see Appendix 4.11 Form for reporting and classification of serious adverse events to the Sponsor.

4.23. Classification of serious adverse events and failure that may lead to significant injury (Sponsor's responsibility)

The Sponsor's permanent representative must make an independent assessment of the seriousness and possible connection with the medical device that is being investigated; see Appendix 4.11 Form for reporting and classification of serious adverse events to the Sponsor. If necessary, this must be done in cooperation with a person or persons with appropriate medical and/or technical qualifications independently of the Principal Investigator.

4.24. Reporting of unexpected serious adverse events to the Norwegian Medical Products Agency (Sponsor's responsibility)

Serious adverse events that may lead to significant injury, and which have a possible connection with the device that is being investigated, must be reported by the Sponsor to the
Norwegian Medical Products Agency. medisinsk.utstyr@legemiddelverket.no without delay. 
Reporting is made on a standard EU form; see Appendix 4.12 Form for reporting serious adverse device effects to the Norwegian Medical Products Agency.

Serious failure by the use of medical devices must be reported in the svikt-system, https://www.melde.no/.

For definitions concerning serious adverse events and substantial injury, see Chapter 7 of this procedure.
 

4.25. Duty of information to subject in the event of injury (Principal Investigator's responsibility)

If a subject incurs an injury or a complication that may be a result of the research project, the Principal Investigator must immediately inform the subject about the injury and about the subject's rights including the right to apply for compensation. The research institution's representative must also be informed promptly.

4.26. Submission of final notification and reports (Sponsor's responsibility)

Reports on the results of the trial shall be forwarded to REC and the Norwegian Medical Products Agency as soon as they are available.

4.27. Archiving of project documentation (Sponsor's and Principal Investigator's responsibility)

Key project documents in accordance with Appendix 4.13 Checklist for archiving of project documentation, shall in the course of the project be filed in a manner that is appropriate for the conduct of the trial. After the project is finished the documentation must be archived together, in a format and location in accordance with the institute's procedures. For storage of research data, see Routine description 6 Storage and handling of data (information security).

4.28. Agreement with subcontractors (Sponsor's responsibility)

Qualified subcontractors may be used to carry out the Sponsor's tasks, such as packaging of medical devices, monitoring, statistical planning and processing, handling of data. Agreements with subcontractors must be in writing. The Sponsor's permanent representative is responsible for ensuring that agreements exist and that subcontractors are qualified for the relevant tasks.

5. Legal basis

• LOV 2008-06-20 no. 44  Medical Research Act
• FOR-2009-07-01-955     Regulations on Organisation of Medical Research
• LOV-1995-01-12-6          Medical Devices Act
• FOR-2009-12-16-1652   Medical Devices Regulations
• LOV-1988-12-23-104      Product Liability Act
• LOV-2018-06-15-38        Act on the Processing of Personal Data

See also:

Norwegian Medical Products Agency    Guidelines on Notification for Clinical Trial of Medical                                                                 Devices in Norway

ISO standard                              ISO/DIS 14155.2 Clinical Trial of Medical Devices for                                                                 Human Subjects - - GCP

6. Appendices

• 2.1 Form for project planning; see Routine description
• 4.1 Form for documentation of Principal Investigator and trial site.docx 
• 4.2. Form for Principal Investigator's delegation of tasks.docx
• 4.3. Checklist clinical trial protocol.docx
• 4.4. Form for study initiation meeting.docx
• 4.5 REK¡¯s information and informed consent templates
• 4.6 REK¡¯s project amendment procedure with checklist
• 4.7.Template for monitoring plan
• 4.8. Monitoring report form.docx
• 4.9.Project close-out form.docx
• 4.10. Investigational medicinal devices accountability form.docx
• 4.11.Form for reporting and classification of serious adverse events reactions.docx
• 4.12.Copy of sae_reporting_form.xlsx
• 4.13.Checklist for filing of project documentation.docx
• 6.3 Form for subject identity list and list of subjects; see Procedure Description 6

7. Definitions