Execution

This section describes practical requirements that apply during the conduct of clinical trials of medicinal products, including documentation, monitoring, reporting and completion of the study.

Establish trial master files

For clinical trials of medicinal products, trial master files shall be established – one for the sponsor and one for the investigator. The files are established at the initial stage of the trial and updated continuously while the study is ongoing.

The trial master files contain both the documentation required to initiate a clinical trial of a medicinal product and documentation generated during the conduct of the trial. ICH-GCP provides detailed information on which documents shall be held by the sponsor and the investigator, respectively, before, during and after the trial. EMA has also developed recommendations on which documents trial master files should contain.

After completion of the trial, the documentation in the files shall be sufficiently complete to allow the study to be fully reconstructed.

• The investigator site file contains documentation that is important for the individual clinical site
• The sponsor trial master file contains the complete documentation for the entire trial

Please note: Information that can identify study participants must not be included in the sponsor trial master file.

Support related to trial master files

• Information on what to include in the clinical trial master file (ICH-GCP E6), EMA website External link.
• Recommendation for what clinical trial master files should contain, EMA website External link.
• Templates for table of contents for clinical trial master files at investigator and sponsor External link.
• Conduct of monitoring

Conduct of monitoring

Monitoring is performed for quality control purposes and is a requirement for clinical trials of medicinal products. Monitoring is carried out by a monitor on behalf of the sponsor. The monitor must not be involved in the practical conduct of the clinical trial at the site.

Competence requirements for monitors

The monitor shall have scientific and/or clinical knowledge of:

• regulatory requirements
• ICH-GCP
• the trial protocol
• the investigational medicinal product being tested
• participant information
• sponsor procedures

The monitor shall verify that the protocol is complied with, that laws and regulations are followed, and that collected data are complete and correctly recorded.

Templates supporting monitoring

Clinical Studies Sweden has developed templates that may be helpful in the planning and conduct of monitoring, particularly when several monitors collaborate within the same study.

Templates that can help in the planning and implementation of monitoring, when several monitors interact within a single study External link.

Notifications in the EU portal CTIS

For clinical trials of medicinal products conducted in accordance with EU Regulation 536/2014, the sponsor shall submit notifications via the EU portal CTIS (Clinical Trials Information System).

The sponsor shall, among other things, notify:

• when the clinical trial of the medicinal product starts
• when recruitment starts
• when the first study participant has completed the first visit
• when recruitment has ended
• temporary interruption of the trial
• early termination of the trial

Notifications shall be submitted within 15 days.

Information on notification in the EU portal CTIS, EUR-Lex website External link.

Report incidents

The investigator in a clinical trial of a medicinal product is responsible for continuously recording and, in some cases, reporting incidents (adverse events) or abnormal laboratory results within the study.

Certain serious and unexpected incidents may need to be reported to the competent authorities via the EudraVigilance database. The procedures for safety reporting shall be clearly defined in the trial protocol.

As safety reporting is important both for study participants and for future patients, procedures for safety reporting must be in place before the clinical trial of the medicinal product begins.

Compile an annual safety report

An annual safety report summarising serious incidents shall be compiled for clinical trials of medicinal products (Annual Safety Report, ASR).

The safety report should be prepared in accordance with ICH guidelines for the Development Safety Update Report (DSUR). The report shall include an assessment of safety and whether the risk–benefit balance has changed during the clinical trial of the medicinal product.

The report is submitted via the EU database CTIS.

Information on annual safety reporting, Swedish Medical Products Agency website External link.

Medical devices in the EU are divided into two regulatory categories that follow different sets of rules. Medical devices are subject to the EU Medical Devices Regulation (MDR). New rules apply in the EU from May 26, 2021, additional rules apply in Sweden from July 15, 2021.

Recommendation to follow good clinical practice

The clinical trial must not start before an approval from the relevant authorities is in place. Read more about notification and application in the Application section. The study must be conducted in accordance with the clinical investigation plan (CIP) approved by the authorities.

The Medical Products Agency recommends that clinical trials of medical devices be conducted in accordance with ISO 14155:2020 Clinical investigation of medical devices - good clinical practice. The standard includes guidance on roles and responsibilities in a medical device clinical trial; you can read more about this in the Planning step. Through an agreement between the Swedish Standards Institute (SIS) and the Swedish Association of Local Authorities and Regions (SKR), all Swedish healthcare professionals have free access to standards on the SIS website, such as ISO 14155:2020.

Free access to standards, SIS website External link.

Medical device perspectives on consent from study participants

For all clinical studies, unless an exception is approved, study participants must provide informed consent in accordance with the Ethical Review Authority's Guidance on Study Participant Information and Consent. In the case of clinical trials of medical devices, additional requirements for patient information and the consent procedure are specified in the EU Medical Devices Regulation and ISO 14155:2020.

In addition, supplementary Swedish legislation must be followed regarding the consent procedure for clinical trials of medical devices involving minors and incapacitated persons. In the case of a clinical trial of a medical device involving children, both legal guardians must give their informed consent on behalf of the child. Minors over the age of 15, who understand the implications of participating in the trial, must also give their informed consent.

• Guidance on study participant information and consent, Ethical Review Authority website External link.
• Patient information requirements and the consent procedure, EU Medical Devices Regulation, EUR-Lex website External link.
• Requirements for consent procedure in clinical trials of medical devices in minors and persons who are incapacitated. Act with supplementary provisions to the EU Regulation on medical devices, Swedish Code of Statutes website External link.
• Patient information requirements and consent procedure in ISO 14155:2020, SIS website External link.

Compilation of documentation in clinical trial master files

ISO 14155:2020 provides information on what study documentation should be prepared in a clinical trial of medical devices. A compilation of the documentation should be kept by both the investigator (clinical trial master file, site file) and the sponsor (clinical trial master file, sponsor file). The compilations should contain all the documents necessary to evaluate the conduct and quality of the study. Once a study is completed, it should be possible to reconstruct it based on the documentation in the clinical trial master files. The site file should contain all documentation relevant to the individual trial site and the sponsor file should contain the cumulated documentation for all participating trial sites. Information that could identify study participants must not be included in the sponsor file.

Initiation visit

Prior to the start of the study, the sponsor and/or monitor should conduct initiation visits to all participating sites or hold a single meeting with all principal investigators and staff. The purpose is to review the clinical investigation plan and all study-related activities with the principal investigators and other staff involved in the conduct of the study, and to ensure that the trial site has all the necessary equipment, resources and documentation, including approval, to start the study. It is recommended that the sponsor documents an overview of the meeting content and a list of participants with names, initials, signatures and function. The monitor should write a report of the meeting.

Handling of a medical device in a clinical trial of a medical device

Medical devices and any comparator devices in a medical device clinical trial must be traceable from the time they are sent to the trial site until they are returned or destroyed at the end of the study.

This means, e.g., that the unique identity of the device, the expiry date, the date of receipt by the investigator and the date of return must be documented.

Medical devices evaluated in a medical device clinical trial must be labelled with the phrase “for clinical trialonly”.

The sponsor has overall responsibility for the medical device and for training staff in the use of the device and the documentation required for traceability. The principal investigator ensures that the medical device is used only by authorised users and in accordance with the clinical investigation plan (CIP) and other study instructions.

Safety reporting of product defects and adverse events

In medical device clinical trials of devices that are not yet CE marked or on devices that are not used for their intended purpose, specific safety reporting should be done during the course of the study. This also applies to trials of already CE marked devices used for their intended purpose if serious adverse events related to study-specific procedures occur.

The reporting of adverse events and product failures is important both for the people participating in the study and for future patients. Reporting processes must be in place before the study starts.

The sponsor is responsible for ensuring that all serious adverse events associated with the use of the medical device, a comparator, or the study procedure are reported immediately to the Medical Products Agency during the course of the study. This also applies to device deficiencies that could have led to serious adverse events if appropriate measures had not been taken or if conditions had been less favourable. The safety reporting is summarised at the end of the study and included as part of the study's final report.

Please see the Publish section for more information on writing a final report. External link.

The sponsor has the overall responsibility for safety reporting, but the investigator is responsible for continuously recording and assessing all adverse events and device failures at the trial site. The investigator makes an assessment of the severity and link between the use of the medical device and the adverse event and reports this to the sponsor.

More information on safety reporting and established reporting timelines can be found in the EU Medical Devices Regulation, MDCG 2020-10/1 and ISO14155:2020.

Guidance on safety reporting in clinical investigations (MDGC 2020-10/1), European Commission website External link.

In studies on CE marked devices used within the scope of the intended purpose of the device, the normal procedures of the healthcare system for reporting adverse events and incidents apply. However, an exception applies to serious adverse events related to study-specific procedures, which must also be reported to the Swedish Medical Products Agency in these studies.

Reporting of adverse events and incidents, Swedish Medical Products Agency website External link.

Medical device perspectives on data collection

The case report form (CRF) created on paper or in electronic format during the planning of the study needs to be finalised before the start of the study, see information on the planning page. The people involved in data collection should have received training on how to use the case report form and within what timeframes data should be recorded. The principal investigator of a clinic certifies that the data collected are accurate, complete, legible and recorded in a timely manner.

Information on case report forms (CRF) External link.

Data generated during the study can be recorded directly in the case report form and then constitute source data. Source data can also be generated via, for example, ECG printouts, laboratory analysis reports or recorded for the first time in patients’ medical records or worksheets, and then transferred to the case report form. It is important to define the source data before the start of the study to ensure consistent data management and preservation of all original data.

Verification of source data is an important part of the quality review carried out by the monitor during a study and is also done in case of inspection by authorities.

All study data, including source data, must be stored securely to serve as a reliable reference for the future.

Information on recommendations for data collection in clinical studies of medical devices, including specific recommendations for electronic case report forms, can be found in ISO 14155:2020.

Conduct of monitoring

Monitoring is conducted as a quality control at the participating trial site. The monitor checks that the staff involved in the study have the right qualifications and prerequisites, that the clinical investigation plan (CIP) and applicable laws and regulations are followed, and that data are correctly recorded in the study participants' case report form (CRF). All monitoring activities are documented in a written report to the sponsor.

Monitoring is a requirement for medical device clinical trials and should be done before, during and after the study. The sponsor should establish a monitoring plan before the start of the study. The scope and frequency of monitoring is based on an evaluation of the risks, design and complexity of the study and is described in the monitoring plan. More detailed information on monitoring can be found in ISO 14155:2020.

Monitoring isconducted by a person independent of the investigator and appointed by the sponsor. A monitor must not be involved in the practical implementation of the study.

More on monitor qualifications External link.

Audit and inspection

An audit means that the sponsor or a third party appointed by the sponsor conducts an audit to evaluate compliance with the clinical investigation plan and applicable laws and regulations for study conduct, data management and reporting. An audit can take place at all parties involved in a study and is performed independently of routine monitoring. The reason for an audit varies and may be as part of the sponsor's quality program, as a check on the effectiveness of monitoring, in connection with suspected misconduct, or in preparation for an inspection by an authority.

Information on audits in ISO 14155:2020, SIS website External link.

An inspection is a review by the regulatory authority overlooking the medical device clinical trial and is an official audit and review of study documentation, equipment, resources, records and quality measures at clinics and other parties involved in the study.

The principal investigator is obliged to make study documentation available upon request of the monitor, auditor or inspecting authority.

Amendments to approved application or interruption of ongoing study

If a substantial amendment to an ongoing medical device clinical trial is required, an application for amendment must be submitted to the Swedish Medical Products Agency, which coordinates the review of the amendment with the Ethical Review Authority. No separate amendment application needs to be sent to the Ethical Review Authority, but a special form for ethical review of the change must be sent to the Swedish Medical Products Agency. The application for amendment to the Swedish Medical Products Agency is made via the same electronic process used for the original application.

Application for amendment, Swedish Medical Products Agency website External link.

Special form for ethical review of amendment application, Ethical Review Authority website External link.

If the study must be stopped for any reason or an individual trial site must be closed prematurely, this must also be reported to the Swedish Medical Products Agency. The reason for the interruption of the study must be documented and may be, for example, due to suspicion of unacceptable risks to the study participants or serious or repeated non-compliance with the study processes by a trial site. If the study is temporarily suspended or prematurely terminated for safety reasons, the Swedish Medical Products Agency must be notified within 24 hours. If the interruption/termination is for other reasons, this must be reported within 15 days. ISO 14155:2020 further describes the activities that should be performed in case of interruption and premature termination of a study.

Completing a study and preparing for report writing

Once a participating trial site has completed the last study activities and recorded all data in the case report form, the monitormakes a close-out visit. The monitor ensures that all data reporting and documentation is accurate and complete, that any questions have been answered, and that surplus materials or medical devices have been destroyed or returned.

The study sponsor is responsible for ensuring that all close-out activities are performed, checking that all study data are complete and accurate, and making final follow-ups if any ambiguities remain. After that, the study database can be considered final and complete, the database can be locked and the statistical analysis can start.

Guidance on close-out activities at participating sites is provided in ISO 14155:2020.

Medical devices in the EU are divided into two regulatory categories that follow different sets of rules. In vitro diagnostic medical devices are subject to the EU 2017/746 in vitro diagnostic regulation for medical devices (IVDR). New rules apply within the EU from May 26, 2022.

Recommendation to follow good clinical practice

A clinical performance study cannot start before an approval has been obtained from the relevant authorities. Read more about notification and application in the Application section. The conduct of the study shall follow the clinical performance study protocol approved by the authorities.

The Swedish Medical Products Agency recommends that clinical performance studies of in vitro diagnostic products are performed according to ISO 20916:2019 “good study practice”. The standard provides guidance on roles and responsibilities in a medical device clinical trial. The main text of the standard as well as the annex on adverse event management should be used for all performance studies, while other annexes such as performance study protocol, investigator's brochure, recommended study documentation are not mandatory for performance studies that only require notification to the Swedish Medical Products Agency.

Through an agreement between the Swedish Standards Institute (SIS) and the Swedish Association of Local Authorities and Regions (SKR), all Swedish healthcare professionals have free access to many standards on the SIS website.

Free access to standards, SIS website External link.

Medical device perspectives on consent from study participants

For all clinical studies, unless an exception is approved, study participants must provide informed consent in accordance with the Ethical Review Authority's Guidance on Study Participant Information and Consent. For clinical performance studies, additional requirements for patient information and the consent procedure are specified in the EU Regulation on in vitro diagnostic medical devices and ISO 20916:2019.

In addition, supplementary Swedish legislation must be followed regarding the consent procedure for clinical performance studies involving minors and incapacitated persons.

Guidance on study participant information and consent, Ethical Review Authority website External link.

Consent procedure requirements for medical device clinical trials involving minors and incapacitated persons, Law with supplementary provisions to the EU Medical Devices Regulation External link.

Patient information requirements and the consent procedure in ISO 20916:2019, SIS website. External link.

Compilation of documentation in clinical trial master files

ISO 20916:2019 provides information on what study documentation should be prepared in a clinical performance study. A summary of the documentation should be available at both the trial site conducting the study and the sponsor. The compilations should contain all the documents necessary to evaluate the conduct and quality of the study. Once a study is completed, it should be possible to reconstruct it based on the documentation in the clinical trial master files. The trial site should store all documentation relevant to the individual trial site, and the sponsor should store the compiled documentation for all participating trial sites. Information that could identify study participants must not be stored by the sponsor.

Initiation visit

Prior to the start of the study, the sponsor and/or monitor should conduct initiation visits to all participating sites or hold a single meeting with all principal investigators and staff. The purpose is to review the clinical performance study protocol and all study-related activities with the principal investigators and other staff who will be involved in the conduct of the study, and to ensure that the trial site has all the necessary equipment, resources, training and documentation, including approval, to start the study. It is recommended that the sponsor documents an overview of the meeting content and a list of participants with names, initials, signatures and function. The monitor should write a report of the meeting.

Handling of in vitro diagnostic products in performance studies

In vitro diagnostic devices and any comparator devices in a clinical performance study must be traceable from the time they are shipped to the trial site until they are returned or destroyed at the end of the study.

This means, e.g., that the unique identity of the device, the expiry date, the date of receipt by the investigator and the date of return must be documented.

In vitro diagnostic devices evaluated in a performance study must be labelled with the phrase “for clinical trial only”.

The sponsorhas overall responsibility for the product and for training staff on how to use the product and what documentation is required for traceability. The principal investigator must ensure that the in vitro diagnostic device is used only by authorised users and in accordance with the clinical performance study protocol and other study instructions.

Safety reporting of product defects and adverse events

In clinical performance studies, specific safety reporting during the course of the study is required by IVD legislation. This also applies to performance studies on already CE marked devices used for their intended purpose in case of serious adverse events related to study specific procedures.

The reporting of adverse events and product failures is important both for the people participating in the study and for future patients. Reporting processes must be in place before the study starts.

The sponsor is responsible for ensuring that all serious adverse events associated with the use of the in vitro diagnostic device, a comparator device or the study procedure are reported immediately to the Swedish Medical Products Agency during the course of the study. This also applies to device deficiencies that could have led to serious adverse events if appropriate measures had not been taken or if conditions had been less favourable. The safety reporting is summarised at the end of the study and included as part of the study's final report.

Information on writing a final report External link.

The sponsor has the overall responsibility for safety reporting, but the investigator is responsible for continuously recording and assessing all adverse events and device failures at the trial site. The investigator makes an assessment of the severity and link between the use of the medical device and the adverse event and reports this to the sponsor.

More information on safety reporting and established reporting timelines can be found in the EU Regulation on in vitro diagnostic medical devices and ISO 20916:2019.

In clinical performance studies of CE marked devices used within the scope of the intended purpose of the device, the normal healthcare procedures for reporting adverse events and incidents apply. However, an exception applies to serious adverse events related to study-specific procedures, which must also be reported to the Swedish Medical Products Agency in these studies.

Reporting of adverse events and incidents, Swedish Medical Products Agency website External link.

Medical device perspectives on data collection

The case report form (CRF) created on paper or in electronic format during the planning of the study needs to be finalised before the start of the study, see information on the planning page. The people involved in data collection should have received training on how to use the case report form and within what timeframes data should be recorded. The principal investigator of a clinic certifies that the data collected are accurate, complete, legible and recorded in a timely manner.

Information on case report forms (CRF) External link.

Data generated during the study can be recorded directly in the case report form and then constitute source data. Source data can also be generated via, for example, ECG printouts, laboratory analysis reports or recorded for the first time in patients’ medical records or worksheets, and then transferred to the case report form. It is important to define the source data before the start of the study to ensure consistent data management and preservation of all original data.

Verification of source data is an important part of the quality review carried out by the monitor during a study and is also done in case of inspection by authorities.

All study data, including source data, must be stored securely to serve as a reliable reference for the future.

Information on recommendations for data collection in clinical performance studies including specific recommendations for electronic case report forms can be found in ISO 20916:2019.

Conduct of monitoring

Monitoring is conducted as a quality control at the participating trial site. The monitor checks that the staff involved in the study have the right qualifications and prerequisites, that the clinical performance study protocol and applicable laws and regulations are followed, and that data are correctly collected and recorded. All monitoring activities are documented in a written report to the sponsor.

Monitoring is a requirement for clinical performance studies and should be done before, during and after the study. The sponsor should establish a monitoring plan before the start of the study. The scope and frequency of monitoring is based on an evaluation of the risks, design and complexity of the study and is described in the monitoring plan. More detailed information on monitoring can be found in ISO 20916:2019.

Monitoring isconducted by a person independent of the investigator and appointed by the sponsor. A monitor must not be involved in the practical implementation of the study.

More on monitor qualifications External link.

Audit and inspection

An audit means that the sponsor or a third party appointed by the sponsor conducts a review to evaluate compliance with the clinical performance study protocol and applicable laws and regulations for study conduct, data management and reporting. An audit can take place at all parties involved in a study and is performed independently of routine monitoring. The reason for an audit varies and may be as part of the sponsor’s quality program, as a check on the effectiveness of monitoring, in connection with suspected misconduct, or in preparation for an inspection by an authority. For more information on audits, see ISO 20916:2019

An inspection is a review by the regulatory authority overlooking the clinical performance study and is an official audit and review of study documentation, equipment, resources, records and quality measures at clinics and other parties involved in the study.

The principal investigator is obliged to make study documentation available upon request of the monitor, auditor or inspecting authority.

Amendments to approved application or interruption of ongoing study

If a substantial amendment to an ongoing clinical performance study is required, an application for amendment must be submitted to the Swedish Medical Products Agency, which coordinates the review of the amendment with the Ethical Review Authority. The application for amendment to the Swedish Medical Products Agency is made via the same electronic process used for the original application.

Application for amendment, Swedish Medical Products Agency website. External link.

Special form for ethical review of amendment application, Ethical Review Authority website External link.

If the study must be stopped for any reason or an individual trial site must be closed prematurely, this must also be reported to the Swedish Medical Products Agency. The reason for the interruption of the study must be documented and may be, for example, due to suspicion of unacceptable risks to the study participants or serious or repeated non-compliance with the study processes by a trial site. If the study is temporarily suspended or prematurely terminated for safety reasons, the Swedish Medical Products Agency must be notified within 24 hours. If the interruption/termination is for other reasons, this must be reported within 15 days. ISO 20916:2019 further describes the activities that should be performed in case of interruption and premature termination of a study.

Completing a study and preparing for report writing

Once a participating trial site has completed the last study activities and recorded all data, the monitormakes a close-out visit. The monitor ensures that all data reporting and documentation is accurate and complete, that any queries have been answered and that any surplus material or in vitro diagnostic products have been destroyed or returned.

The study sponsor is responsible for ensuring that all close-out activities are performed, checking that all study data are complete and accurate, and making final follow-ups if any ambiguities remain. After that, the study database can be considered final and complete, the database can be locked and the statistical analysis can start.

Guidance on close-out activities at participating trial sitesis provided in ISO 20916:2019.

Information on data management External link.

Advanced therapy medicinal products (ATMP) are human medicines, based on genes, tissues or human cells. They offer ground-breaking new opportunities for the treatment of diseases and injuries. More information about advanced therapy:

• For guide/templates and regulatory guide, ATMP project website External link.
• Classifications, regulatory information, European Medicines Agency website External link.
• About the product area: advanced therapy and joint links (in Swedish), Swedish Medical Products Agency’s website External link.
• E-course: Introduction to advanced therapies (in Swedish), Swedish Academy of Pharamceutical Sciences website External link.