Procedure 3 Responsibilities and tasks in connection with clinical trials of medicinal products

1. Purpose

The purpose of this procedure is to ensure that research projects subject to the Norwegian Regulations relating to Clinical Trials on Medicinal Products as well as the Norwegian Health Research Act are planned, organized, initiated, implemented and completed, including management both during and after completion and mediation of the results, appropriately and in accordance with applicable law and in accordance with UiO¡¯s policy for clinical trials of medicinal products. This includes, a sound internal evaluation, determination of which legislation that should apply, an evaluation of which role(s) UiO should possess in the project and which quality system that is to be applied. 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 subject to the Health Research Act that involves the administration of medicinal products to humans. Clinical trials of medicinal products that are conducted in collaboration with other institutions or other cooperating partners such as for example university hospitals or the pharmaceutical industry should primarily be conducted with a cooperating partner as the sponsor (responsible for research), and as a consequence of this in accordance with the cooperating party's quality assurance system. This should be laid down in an agreement (for example a framework agreement, cooperation agreement or project agreement). The agreement must describe roles and responsibility, especially it must be specified which of the parties has the sponsor responsibility pursuant to the legislation.

For clinical trials of medicinal products which are being conducted in cooperation with the primary care services or other health care institutions (f.ex. general practitioners, specialist care practices, nursing homes, rehabilitation homes or other institutions) it will be natural for the UiO to be the sponsor. If it is planned for the UiO to be the sponsor, this must be clarified with the representative of the person responsible for research. This clarification should take place in connection with the internal presentation and evaluation of the project (See Routine 2 Responsibilities and tasks of the project leader).

3. Responsibilities

Pursuant to the legislation on medicinal products, responsibility in clinical trials of medicinal products is divided between two parties: the Sponsor and the Investigator (for definitions, see Section 7 of this procedure). The UiO may formally possess both roles in one and the same clinical trial, but will according to UiO¡¯s policy normally possess the role of investigator while a cooperating partner will possess the role of sponsor. According to the pharmaseuticals legislation, the Sponsor has extended responsibility compared with the responsibility of the person or body responsible for research pursuant to the Health Research Act. The UiO is not organized to take on this responsibility.

If, as per an understanding with the representative of the person/institution responsible for research, it is still decided that the UiO should possess both roles (sponsor and principal investigator), resources must be allocated for research support from an external partner (third party provider). This is necessary to secure compliance with the obligations of the sponsor towards the authorities.

The representative of the responsible for research

has the responsibility to clarify the sponsor¡¯s responsibility in cooperation with the relevant administrative and professional competence for the trial in question. A potential decision that the UiO is to possess the role of sponsor must be confirmed at the faculty level or similar.

At the decision of the UiO as the sponsor:
Sponsor of clinical trials of medicinal products

is responsible for the submission of an application to the Norwegian Medical Products Agency for approval. An application must be submitted by the sponsor in the European portal CTIS (Clinical Trial Information System) which has been established for such applications. Access to the portal requires special training and must be created with EMA (the European Medicines Agency).

https://legemiddelverket.no/godkjenning/klinisk-utproving/ny-forordning-for-kliniske-studier/clinical-trials-information-system-ctis

The application for a clinical trial of medicinal products in the CTIS has comprehensive requirements for information and documentation which must be provided by the project leader in cooperation with the sponsor. Among other things this includes

• application form
• references to research previously conducted by others
• agreements with previous/other sponsors
• covering letter in 7 sections and 9 subsections, with references to other enclosures Protocol, ~ 50 detailed sections and 7 subsections (biostatistics)
• documentation of production of placebo or reformulated medicinal product

The application must be followed up in the CTIS with, among other 

• Application for amendments to the research plan 
• Notifications of adverse events 
• Interim reporting and close-out reporting 
• Notification of serious deviations from the research plan or procedures ?serious breaches? 

In addition, the sponsor (representative of the responsible for research) is responsible for

• ensuring that the project (trial) has a qualified Principal Investigator (Project Manager)
• preparing a project protocol in cooperation with the project manager (Principal Investigator)
• ensuring that trial subjects are insured in the Drug Liability Association (Norsk Legemiddelforsikring AS)
• documenting that the trial site has satisfactory facilities
• ensuring that a study initiation visit is held
•  receiving from Investigator and classifying reports of adverse events
• regulatory archiving and storage of Sponsor's project documentation in accordance with applicable laws and the Sponsor¡¯s operating procedures
• handling and processing of data
• ensuring that necessary investigational medicinal products areis available for the clinical trials
• ensuring that there are written agreements with all investigators in the project
• signing the project plan (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 that the trial is monitored (supervised) by a qualified person (monitor). This person must be independent of the investigator (the project leader), i.e. be employed or have a written agreement with the sponsor specifying the tasks which should be completed in connection with the monitoring. A plan for the monitoring (monitoring plan) should also be available (see also section 4.15).

The Principal Investigator (Project Manager) is responsible for:

• preparing a project protocol in cooperation with the Sponsor
• to provide/prepare additional attachments required for the application and follow-up in CTIS, 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
• internal submission to the representative of UiO¡¯s responsible for research, in accordance with the unit's procedures and UiO¡¯s routine for presentation for external funding when relevant
• communication with the external or internal Sponsor's representative and with UiO¡¯s authority for exercising the processing responsibility 
• registering the project in UiO¡¯s system for  health research overview, FORSKPRO
• to notify Sikt of the project
• ensuring that trial subjects give informed consent
• keep a complete list of the trial subjects
• the daily conduct of the clinical trial
• communication with Sikt
• to contribute to the sponsor¡¯s communication with the authorities via CTIS
• overall accountability of the investigational medicinal products used in the clinical trial
• storage and handling of investigational medicinal products
• ensuring that data are obtained and recorded accurately
• regulatory filing and storage of the Principal Investigator's project documentation in accordance with applicable legislation and UiO's operating procedures
• reporting of adverse events to Sponsor
• ensuring that the trial is conducted in accordance with approved conditions
• ensuring that amendments to the trial protocol are approved in CTIS, and also to notify Sikt, before they are implemented
• ensuring that research data is handled and stored in accordance with applicable laws and UiO's procedures
• information to trial subjects in connection with harm or complications
• ensuring a final report and if appropriate, other reports are submitted in CTIS

4. Description of tasks

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

Each trial site in a clinical trial must have a Principal Investigator with medical or odontological qualifications. Principal Investigator's qualifications must be documented by means of a CV.

Sponsor's permanent representative must determine whether the trial site fulfils the requirements for conducting the protocol.  This assessment must be documented according to Appendix 3.1 Form for documentation of Principal Investigator and trial site

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

In trials on medicinal products that are cooperation projects with other institutions, research responsibility must be defined and a written agreement must be in place before the project starts. The principal rule is for the UiO that the cooperating institution should possess the role of sponsor. Sponsor (institution responsible for research) and Principal Investigator (Project Manager) shall be named in the agreement. Principal Investigator must have appropriate research qualifications and experience for the project in question. A statement It should be provided which quality system should be followed for the project. If the cooperating institution has the role of sponsor, all evaluations (prior to initiation and at amendments) should be done in cooperation between the UiO and the sponsor.

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 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 team members' qualifications must be documented pursuant to Appendix 3.2 Form for Principal Investigator's delegation of tasks.

4.4. Insurance of trial subjects (Sponsor's responsibility)

Special insurance pursuant to Chapter 3 of the Product Liability Act is a statutory requirement for clinical trials of medicinal products. When the trial is being conducted in collaboration with
a pharmaceutical company, the company's insurance may apply.  Where a pharmaceutical company's insurance cannot be invoked, separate insurance must be established in the Liability for Drugs Association. Documentation of insurance must be archived with the project documentation.

4.5. Internal submission of the project (responsibility of the project leader)

In connection with planning of the project, it must be submitted to the representative of the responsible for research at UiO, in accordance with the faculty's or institute's procedures and the procedure for submission in connection with external financing when this is relevant. This submission and the assessment of the representative of the institution responsible for research must be documented in accordance with Procedure description 2, Attachment 2.1. Project planning and execution form, and registered in ForskPro. 

The assessment shall comprise the following points, applicable to internal presentation of all health research projects:

• Principal Investigator's/the project manager¡¯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

In addition, for trials of medicinal products an evaluation of  

• whether the cooperating partners are relevant and qualified
• which institution should possess the role of sponsor

Clinical trials of medicinal products 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 representative of the responsible for research, it is decided that UiO should possess the role of sponsor, resource should be allocated for use for 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 (Responsibility of the Principal Investigator/ project manager)

Before the project is sent to CTIS for approval, 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 3. 3.
Checklist trial protocol. All documents must have version control, i.e. version number and date. In clinical trials there must always be a separate trial protocol which must be signed by Sponsor and Principal Investigator (national coordinating investigator in multi-centre trials).

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

Before the clinical trial commences, the necessary approvals must be obtained from the
CTIS. The submission via the CTIS-system comprises applications both to the medicines agency and the ethic¡¯s committee (REK), and approval will be received as a common decision. Applications in CTIS must be complete and have appended a final, signed version of the trial protocol and a final, dated version of other appendices. Sponsor is responsible for sending an application to CTIS, for following this up and for further communication with the CTIS/Norwegian Medical Products Agency.

REK has established separate committees for the evaluation of clinical trials of medicinal products and medical devices, REK_KUMLU

The website of the Norwegian Medical Products Agency (NOMA), with links the European websites
(http://www.legemiddelverket.no/English/Sider/default.aspx) 

REK_KULMU¡¯s website, for the committees for clinical trials of medicinal products and medical devices.

CTIS will be used throughout the life cycle of a clinical trial, including notifications of amendments, reporting and inspection.

4.9 Notification to Sikt (responsibility of the project leader)

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

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

After the project has been approved by CTIS, 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 a 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 execution and schedule for the trial. All investigators and other project team members must attend these meetings. The meeting contents and attendees must be documented in accordance with Attachment 3.4 Initiating meeting form. Before the first trial subject is informed and invited to take part in the trial, the following documents must be in place:

• Signed trial protocol
• Signed financial agreements
• Final approvals from CTIS, as well as an assessment by Sikt

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

All trial subjects must receive information about the research project and be asked to consent to participation pursuant to the approval in CTIS. Information and informed consent forms must be prepared according to REK's templates; see Appendix 3.5 REK's templates for information and consent, with adaptation to the requirements in CTIS . Consents must be documented by means of the date and signature of the trial subjects, who must also be given a copy. In the event of amendments to the execution of the project or the application 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 together with the amendment application in CTIS (ref. point 4.9) and must be approved before it is used.

Investigator must keep a complete  Subject identity list of the persons who are asked to take part in the trial, 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 overview of trial 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 3.7, CTIS¡¯ 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 responsible¡¯s representative if this is a part of the institute's/group's procedures.

A list of the types of amendment that require new approval may be found on REK's website;
https://rekportalen.no/#hjem/s?ke_REK

Appendix 3.6 REK¡¯s routine for project amendment with checklist.
 

4.14 Notification of a change in the processing of personal data

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

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

Sponsor is to appoint an independent monitor (for definition, see Section 7 of this procedure) to monitor the execution and progress of the clinical trial, with focus on the following areas:

• Protection of the trial subjects' rights
• Quality of collected data
• Technical equipment used in the clinical trial
• Investigational medicinal product accountability
• Other documentation that is necessary in accordance with 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 monitor should be independent of the investigator/project leader, ie. there shall not be any organisational connections to this person.

The scope and the frequency of the monitoring is described in a monitoring plan; see 
Appendix 3.8 Template 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 to be sent to Sponsor's permanent representative; see template in Appendix 3. 9 Form for monitoring report
The last monitoring visit in connection with the closing of the trial must be reported by means of Appendix 3.10 Project close-out report.
 

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

Investigator must establish and file source documents for each trial subject. As a minimum the source documents must contain documentation of the trial subject's case history /state of health, documentation of each follow-up visit in the trial, documentation of the duration of exposure to the medicinal product and the dose, and printouts from laboratory tests and any other examinations generating written results. The registration form which is prepared for the trial may be part of the source documentation.

4.17. Compliance with requirements regarding storage of medicinal products (Principal Investigator's responsibility)

Principal Investigator must ensure that all medicinal products used in the clinical trial are stored in accordance with the manufacturer's specifications of the holder of the marketing authorisation as given on the packaging. Access to the investigational medicinal products must be restricted to project team members who have been delegated these tasks in the trial; see Appendix 3.2 Form for Principal Investigator's delegation of tasks.

4.18. Packaging and delivery of investigational medicinal products (Sponsor's responsibility)

The sponsor shall arrange for delivery to Investigator of investigational medicinal products that are packaged and labelled according to regulations and in the right quantity according to the clinical trial protocol. In those cases where UiO has sponsor responsibility, an agreement should be entered into with a pharmacy or other stakeholder with manufacturing authorisation for packaging and labelling of medicinal products for clinical trials.

4.19. Drug accountability (Principal Investigator's responsibility)

Principal Investigator must document the quantity of investigational medicinal product that is delivered to or procured for the trial site, the amount used in the trial, how much remains after the conclusion of the trial and how the unused medicinal product is handled. This also includes medicinal product that is returned by trial subjects. Used and returned amount of medicinal products must be documented for each trial subject in accordance with Appendix 3.11 Investigational Medicinal Product Accountability Form

4.20. Information security (Principal Investigator's responsibility)

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

4.22. Adverse event reports (Principal Investigator's responsibility)

Adverse events must be documented by Principal Investigator.  The registration form that is prepared as an appendix to the research protocol is used for this purpose.

If Principal Investigator regards the event as serious, a form for reporting of serious adverse events must be sent to Sponsor's representative within 24 hours; see Appendix 3.12
Form for reporting and classifying serious adverse events / reactions.

4.23. Classification of serious adverse events (Sponsor's responsibility)

Sponsor's representative must make an independent assessment of the seriousness and possible connection with the trial product; see Appendix 3.12 Form for reporting and classification of serious adverse events / reactions. If necessary, this must be done in collaboration with a person or persons with appropriate medical qualifications independently of Principal Investigator. If Sponsor's permanent representative considers that there is a possible connection (possible adverse reaction), an assessment must also be made of whether similar events are described as adverse reactions in the product documentation. For medicinal products with marketing authorisation, this will be the summary of product characteristics approved by NoMA.

4.24. Reporting of unexpected serious events (SUSARs) to medicinal agencies (Sponsor's responsibility)

The Sponsor should report such events in the EudraVigilance database. 

Possible serious adverse reactions that are not described in the product documentation, and which are lethal or life-threatening (SUSARs), must be reported by Sponsor to EudraVigilance within seven (7) days. SUSARs that are not serious or life-threatening must be reported by Sponsor within 15 days. For definitions concerning serious adverse events, see Section 7 of this procedure.

Access to reporting in EudraVigilance is based on training and certification.

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

If a trial subject incurs harm or a complication that may be a result of the research project, Principal Investigator must immediately inform the trial subject of the harm 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 report and reports (Sponsor's responsibility)

A close-out report must be registered in CTIS as soon as the last trial subject has finished participating in the trial, and at the latest by 15 days. Reports of the results of the trial must be uploaded in CTIS as soon as they are available, and at the latest one year after the last trial subject has finished participating in the trial. 

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

Key project documents in accordance with Appendix 3.13 Checklist for archiving of project documentation shall in the course of the project be filed in a manner that is suitable for the execution 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 Sponsor's tasks, such as packaging medicinal products, monitoring, statistical planning and processing, handling of data.
Agreements with subcontractors must be in writing. Sponsor's permanent representative is responsible for ensuring that agreements exist, that subcontractors are qualified for the tasks in question and for following up in case of changes to the agreements.

5. Legal basis

• LOV 2008-06-20 no. 44 Act on medical and health research (the Health Research Act)
• FOR-2009-07-01-955 Regulation on organisation of medical and health research
• LOV 1992-12-04 no. 132 Act on Medicinal Products etc. (the Medicinal Products Act)
• FOR-2009-10-30-1321 Regulation relating to Clinical Trials on Medicinal Products for Human Use
• LOV-1988-12-23-104 Product Liability Act
• LOV 2018-06-15-38 Act on the Processing of Personal Data

6. Appendices 

• 3.1. Form for documentation of Principal Investigator and trial site - docx
• 3.2. Form for Principal Investigator's delegation of tasks - docx
• 3.3. Checklist Clinical Trial Protocol - docx
• 3.4. Initiation meeting form - docx
• 3.5. Template for informed consent (Regional Committees for Medical and Health Research Ethics site) - html
• 3.6. Procedure for project amendments, with checklist - html - (Regional Committees for Medical and Health Research Ethics site)
• 3.7. Procedure for project amendments, with checklist - html (Norwegian Medical Products Agency site) - (in Norwegian)
• 3.8. Template for monitoring plan
• 3.9. Monitoring report form - docx
• 3.10. Project close-out form - docx
• 3.11 Investigational medicinal product accountability form - docx
• 3.12. Form for reporting and classification of serious adverse events/ reactions - docx
• 3.13. Checklist for filing of project documentation - docx

See also in-depth review of the GCP requirements ((Good Clinical Practice).

7. Definitions in the Health Research Act and Regulations on Clinical Trials