Substantial insurance fees.
Application fees.
Monitoring abroad, including possible coordinating role for monitoring.
Drug distribution, import.
Sending/distribution of samples/sample equipment.
Data management cost will increase with:
- PROMs in different languages.
- Lack of monitoring coordination resulting in communication problems.

Feasibility

Evaluating the inclusion of a specific country in a trial requires assessment of the potential principal investigators (PIs) in that country and/or their affiliated Clinical Trials Unit (CTU).

For the sponsor, it is important to get an overview of the qualifications, experience and availability of the PIs and site personnel, and affiliated CTU if applicable, and their institution’s experience in clinical trials. Also, specifics of the trial and regulatory aspects should be considered.

The sponsor should identify trial specific risks that may vary from country to country or site to site. Examples of such risks may be related to eligibility criteria, drug availability and the possibility to perform the trial procedures.

A Site Feasibility form, customised per trial, can be used to address the above mentioned issues. Also some of the answers can be used in the Site Suitability Forms that need to be submitted when applying Ethics Committees (EC). When adapting the form, considerations should be given to what the sponsor will perform, and which tasks need to be delegated to PIs/CTUs. The responsibility for the tasks will always reside with the sponsor.

The completed form will form a basis for the contract between sponsor and CTU/principal investigators (PIs).

Sharing of data

If data is anticipated to be shared with other institutions, this should be reflected in the informed consent document, the application to ECs and the agreements between involved parties.

A suitable data sharing platform is recommended. An example of such a platform is Tjeneste for sensitive data (TSD), owned by the University of Oslo. It is important to act pursuant to the applicable procedures at sponsor institution, hereunder determine the roles and responsibilities of the parties related to the data transfer.

Before exporting data to the platform, a data minimization procedure should be followed in order to remove data that potentially can contribute to identification of study participants. This applies especially to demographic data.

Applications and correspondence with authorities

Legal differences between countries and their consequences for the trial should be identified by the Site Feasibility form. For countries in the EEA, as well as a few other countries such as Switzerland, Turkey and United Kingdom, information can also be sought from ECRIN's tool kit, but should be verified. Items that usually require attention are detailed in the sections below.

Regulation 536/2014 should facilitate regulatory processes within the EEA. Language requirements for part I can be found in Questions and Answers Document - Regulation (EU) 536/2014, Annex II. Links to ethics committees in the different countries are listed in Annex III.

For applications in the EEA, the Clinical Trial Information System (CTIS) will be used for application and further communication with competent authorities and ethics committees. The sponsor can provide the PIs/CTUs with “preparer” roles for part II.

The sponsor should have a contract with a PI or a CTU, ensuring they will provide necessary documentation for Part II.

For countries outside the EEA, it is advisable to let a PI/CTU manage the correspondence with local authorities. The PI/CTU will then need a Power of Attorney from the sponsor.

Insurance

It is a sponsor responsibility to ensure that the participants in a clinical trial are insured in all participating countries. Whether low-intervention trials, as defined in Regulation 536/2014, need a specific insurance for the trial varies among countries.

Some countries, such as Spain and Norway, have legal requirements as to which insurance should cover the trial. In Denmark, there is no need for additional insurance for clinical trials. In Sweden, there is generally no need for additional insurances if the drug company (manufacturer/importer) already has an insurance. If needed, most hospitals/hospital regions have insurances that can cover academic drug trials. For other European countries, ECRIN may advise on insurance providers that can be used in the different countries.

It is advisable to contact an insurance mediator (forsikringsmegler, e.g. Norsk Forsikringsmegling). Mediators in Norway can recommend mediators abroad. It is advisable to involve as few insurance companies as possible per trial.

Insurance can be costly and may require a call for tenders (anbud). Features such as uniqueness of the insurance, time constraints etc. might provide grounds for dispensation. The organisation’s procedures should be followed.

Both providing the insurance and paying for it could be delegated to one PI, but the responsibility for ensuring insurance is in place resides with the sponsor.

Informed consent document

The format and the content of the informed consent document vary across countries. The sponsor should provide a minimum set of information that should be included in all documents in English.

Ideally, the sponsor should translate back the final informed consent document from other participating countries to ensure that the minimum set of information is correctly translated and that any other information written is acceptable.

If this is not possible, the responsibility for correct translation would be given to the entity translating and adapting the document to national requirements. This should be documented in the agreement.

Safety reporting

As of 31 January 2022, the EEA has a harmonised SUSAR reporting to the competent authorities solely through Eudravigilance, also for trials approved under the Directives 2001/20/EC and 2008/28/EC (CTD). There might be national ethics committees wanting reporting (they are advised to review the relevant national legislation). This information should be collected using Safety Reporting Specifics - Template.

It might be advisable to have a local safety officer (LSO) in some countries. Allocated tasks might be:

Translation of additional documents such as autopsy reports.
Correspondence with ethics committee if there are special safety reporting required for ethics committees in some EEA countries and/or ethics committees and competent authorities if outside the EEA.

The potential benefits of having an LSO should be weighed against the complexity of having even more persons involved. A local PI or a person at a local CTU might have that role.

Risk evaluation

As for all drug trials, the sponsor must perform a risk evaluation of the trial, including organisation and management. Together with the responses from the site feasibility forms, the sponsor should consider whether further risk assessment should be undertaken for each/some country(ies)/site(S).

Monitoring

Monitors from the CTUs at the Norwegian university hospitals rarely monitor abroad. Providing monitoring is therefore usually delegated to PIs/CTUs. See Monitoring providers in Scandinavia. For other countries in the EEA, the ECRIN Correspondent may be contacted for advice.

For trials that will mainly be monitored off-site, sites abroad may be monitored by monitors located in Norway if the monitor is familiar with local legislation and language. It is however seldom acceptable to have exclusively off-site visits. Especially high recruiting sites should have some on-site visits.

Monitoring in all countries should be according to the monitoring plan provided by the sponsor. The sponsor can decide whether the English versions of the NorCRIN monitoring report templates should be used or whether the monitors in other countries are allowed to use their own templates. The first option is the preferable. If the latter is chosen, the sponsor should make sure the templates fulfill the documentation required by the monitoring plan. Monitors abroad should be provided and asked to follow Monitoring for Monitors - SOP 1.15.a.

Some countries, such as Denmark, need to have a monitoring plan in local language. The translation should be reviewed by sponsor.

The sponsor should establish monitoring agreements with all monitoring facilities. If the monitor is not employed at the sponsor institution, the sponsor should ensure a Data Processing Agreement (DPA, Databehandleravtale) is signed if not included the monitoring agreement.

The sponsor should have a dedicated person who has thorough knowledge in Good Clinical Practice (GCP), and preferably hands on monitoring experience for the coordination of the monitoring in all participating countries. It is recommended that the lead monitor in Norway is given that role. The tasks should be specified in the monitoring agreement together with the name of the person performing the tasks. Examples of tasks are:

Forward documents such as risk evaluation, monitoring plan and agreement with DPA.
Train the monitors.
Ensure training in the eCRF for monitors and relevant site staff.
Review of monitoring report templates if other than NorCRIN templates are used.
Review of monitoring reports, preferably before they are sent to site.
Inform the coordinating investigator about important issues that either may qualify as serious breaches, impact the risk evaluation or otherwise require action.
Be the main contact point for all monitors.

The tasks are time consuming and should be budgeted for and accounted for when assigning a person to the task.

Also, it is recommended that a person from a site abroad/CTU is given the task to assist in meetings with translation of or conducting of meeting, e.g. start-up meeting.

Such additional tasks should be specified in an agreement.

Agreements

Contracts must be legally and economically sound as well as adapted to the characteristics of the trial. Most often this will require competence from legal personnel and personnel working with grants, in addition to the study team.

Contracts should preferably be between sponsor and the different sites for sponsor to have a complete overview over commitments (as opposed to PIs/other signing contracts in a given country on behalf of the sponsor).

The exception could be in trials where the participating countries are given specific sub-studies, national grants or are acting as co-sponsors.

In general, the sponsor agreement templates should be accepted by the participating sites. Some sites will not accept anything else than their own template. The institutions’ procedure for review and signing of contracts should be followed.

Investigational medicinal product (IMP)

Labelling

If there is a need for labelling, the sponsor should retrieve the languages required in the participating countries from Questions and Answers Document - Regulation (EU) 536/2014 , Annex II. There might be limitations as to how many languages can be included on one IMP unit.

Import of Investigational Medicinal Product

If the supplier in the EEA is responsible for importation to Norway, the agreement with the pharmacy should specify:

That the supplier is responsible for import.
That the supplier is either manufacturer (MIA no.) or wholesaler (WDA no.).
The address from which the IMP is sent.

If the pharmacy is the importer, the agreement with the pharmacy should specify:

That the pharmacy is responsible for importation.
That the supplier is either manufacturer (MIA no.) or wholesaler (WDA no.).
The address from which the IMP is sent.
Conditions for transportation (Incoterm conditions).
That a separate pharmacy import agreement is to be signed between sponsor and pharmacy. Oslo Hospital Pharmacies have a template for import agreement.

Preferably, the IMP exporter should be responsible for transportation to the pharmacy.

If the trial includes several countries in EU, it is recommended to have a drug distributor in EU.

Australia requires IMP to be shipped to a depot in Australia before further shipment to pharmacies/sites.

In order to return IMP, the exporter should be authorised by law (manufacturers and wholesalers) or should have been given an approval for exportation by the competent authority.

Central facilities

Non-commercial sponsors rarely use central laboratories for safety assessments as opposed to commercial sponsors.

Central biobanking or other procedures such as central radiology review for research purposes will require study specific procedures detailing e.g. collection, storage, sending, analyses etc. Sending of biobanks across borders may require use of couriers able to meet the storage conditions for the samples. Most hospitals have agreements in place with specific couriers. Requirements should be detailed in the site agreement if not included in the protocol or other agreement and should include where data/material is to be sent. The responsibility for the shipment resides with the sender.

Start-up

Depending on the countries and language skills, it may be advisable to get assistance from a local person. If that person is to conduct the meeting alone, the sponsor should provide extensive training material and ensure the local trainer is well trained. The sponsor should be readily available for questions.

Recruitment and delivery phase

Inclusion of additional countries

Please review all items described under the section "Planning phase".

Reporting and notifications

The sponsor should use the information gathered in the planning phase using the Site Feasibility forms and the Decision (vedtak) given by each participating country to ensure all requirements are met. The Decision may refer to other documents such as Final Assessment Reports and/or RFI responses.

This includes the period approved by EC for data processing. In Norway, the period should include all publications created using trial data, including explorative endpoints.

Agreements should be in place for any export of data or biological samples.

The number of participating countries significantly increase the complexity of the trial and time needed for coordinating all activities prior to database lock.

Maintenance of the Trial Master File

Sponsor is responsible for keeping an updated archive of the study documentation. Compiling and maintenance of the TMF in a multinational study requires detailed tracking as the amount of documentation will otherwise be unmanageable. This is an ongoing task during the course of the study and should not be postponed till the end of the trial. A common folder structure and preferred naming convention shared by sponsor to be used by all sites/countries will facilitate this task.