Planning

This information applies to clinical trials of a medicinal product. It summarises authorisation requirements, allocation of responsibilities in accordance with GCP, and basic requirements for data management.

Authorisation and trial protocol

A clinical trial of a medicinal product requires authorisation from the Swedish Medical Products Agency. Guidance on the Agency’s website can help you determine whether your medicinal product study constitutes a clinical trial and therefore requires authorisation.

A trial protocol must be enclosed with the application. The trial protocol is the basis for uniform conduct and must contain all the information needed for participating clinics to conduct the trial of the medicinal product properly. Requirements for the content of the trial protocol are laid down in Regulation (EU) No 536/2014 on clinical trials of medicinal products for human use.

Clinical Studies Sweden has developed a template for trial protocols.

Links

• Find out if your study requires approval, the website of the Swedish Medical Products Agency External link.
• What to submit for an application for a clinical trial of a medicinal product, the website of the Swedish Medical Products Agency External link.
• Template for the trial protocol (including help text) External link.

Roles and responsibilities under ICH-GCP

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for clinical trials of medicinal products. The standard sets out requirements for how trials are designed, conducted, documented and reported. The purpose is to protect the rights, safety and well-being of trial participants and to ensure reliable trial data.

For clinical trials of medicinal products, GCP is defined by the International Council for Harmonisation (ICH). In accordance with ICH-GCP, Regulation (EU) No 536/2014 and applicable national legislation, roles and responsibilities must be allocated before the trial is initiated.

Links

• ICH-GCP, International Council for Harmonisation (ICH) website External link.
• EU Regulation (536/2014) on clinical trials of medicinal products in humans and national legislation (CTR), EMA website External link.

Sponsor

The sponsor is the person, company, institution or organisation responsible for initiating, organising and arranging the funding of the trial. In some cases, an individual may be both the sponsor and the principal investigator, in which case he or she is both initiating and managing a clinical trial of a medicinal product. The role thus includes the obligations of both the sponsor and the principal investigator.

Responsibilites
The sponsor has overall responsibility for the conduct of the trial of the medicinal product and is responsible for, among other things, that:

• all regulatory approvals are in place before the trial of the medicinal product starts
• there are written instructions for work, quality control and quality assurance
• the instructions are followed
• study participants are guaranteed financial protection through insurance or other means

The sponsor may delegate all or part of its tasks to an individual, a company, an institution or an organisation, but the sponsor retains responsibility for the conduct and reporting of the trial of the medicinal product in accordance with the applicable approvals and regulations.

Checklist for sponsor responsibility (In Swedish) External link.

Risk assesment
In accordance with ICH-GCP, the sponsor must perform a risk assessment of the clinical trial and, based on this, determine which risks need to be managed and how quality control of the trial should be carried out. Further information is available in ICH-GCP E6.

Links

• Risk analysis template (In Swedish) External link.
• Efficacy Guidelines, ich.org External link.

Monitor

The monitor is a person appointed by the sponsor whose responsibility is to oversee (monitor) the progress of a clinical trial of a medicinal product by, e.g.:

• ensuring on-site that the trial of the medicinal product is conducted, documented and reported in accordance with the protocol, GCP and applicable regulatory requirements
• submitting a written report to the sponsor after each site visit and to report other medicinal product trial-related communications

Competence requirements
In order for the monitor to be able to supervise a trial of a medicinal product, in addition to having prior scientific and/or clinical knowledge, he or she needs to have knowledge of:

• the product to be tested
• the protocol
• Sponsor procedures
• GCP
• regulatory requirements

Independence
The monitor must be independent from the conduct of the medicinal product trial in the clinic.

Investigator

The investigator must be a licensed medical or dental practitioner and have the necessary qualifications in terms of education, training and experience to take responsibility for the conduct of the trial and the health and safety of the trial subjects, including documented training in GCP.

Responsibilites
The investigator must, e.g.:

• provide the conditions to recruit the agreed number of study participants and allocate sufficient time to be able conduct the trial of the medicinal product
• appoint qualified staff to assist in the conduct of the trial of a medicinal product and also supervise delegated staff to ensure all processes
• ensure that delegated staff receive appropriate training on the trial of the medicinal product
• ensure that information about the trial of the medicinal product is provided and that consent to participate is obtained according to the applicable rules
• establish procedures to store all documentation from the trial of a medicinal product and allow supervision and revision
• allow monitoring and auditing

Support

• Checklist for investigator responsibility (In Swedish) External link.

Delegation
The investigator has overall responsibility for the trial of a medicinal product, but may delegate tasks provided that the delegation is in writing. Therefore, a signature and delegation list will need to be established and updated if there are changes of personnel during the trial of the medicinal product. A task must first be delegated before it can be performed by a person other than the investigator.

Principal investigator
If there is more than one investigator at a trial site, the sponsor may appoint one of them as principal investigator.

Data management and archiving

Data on study participants in a clinical trial of a medicinal product are collected using a Case Report Form (CRF), which may be paper-based or electronic (eCRF). An eCRF may form the basis of the database used for analysis, while paper CRFs must be converted into electronic form at a later stage.

Trial documentation must be stored and remain readable for at least 25 years after the clinical trial has been completed and reported.

Plans for data management (Data Management Plan, DMP) and data validation (Data Validation Plan, DVP) must also be established.

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.

The design of the medical device study

The design of a medical device study is based on the research question or hypothesis to be answered or tested. The study should be designed to ensure that the data collected are of good quality and can be used to answer the applicable research question. The research question and study design may vary depending on the purpose of the study and also on the stage of development of the medical device. You can read more about different study designs and statistical aspects in ISO14155:2020 Annex I and on the Analysis page of this website.

• Information on setting up a research question or hypothesis on the Idea page
• Standard ISO 14155:2020, SIS website External link.

Information on study design and statistical aspects on the Analysis page

In addition to considering scientific aspects, there is a need to ensure that the design with best scientific approach is also ethically and practically feasible. It may also be useful to consider how the study design affects the quality of the data collected. A complex study design may require more training for users and staff or an extensive monitoring plan to avoid data quality issues compared to a design that largely follows normal healthcare procedures.

Medical device aspects of ethical review

In addition to the requirements set by the Ethical Review Authority for the written information to be provided to the study participants, the EU Regulation on medical devices and ISO 14155:2020 provide specific recommendations on the information to be provided to participants in a medical device study.

EU regulation on medical devices External link.

Standard ISO 14155:2020, SIS website External link.

Regarding insurance for study participants, there are also circumstances specific to medical device studies. If the studies are carried out in the healthcare entity's facility, the patient insurance that the healthcare entity is obliged to have applies. However, there is no equivalent to Swedish Pharmaceutical Insurance for medical devices.

Will the study be reviewed by the Swedish Medical Products Agency?

Medical device clinical trials must be notified or applied for to the Swedish Medical Products Agency. Clinical trial of a medical device which:

• is CE marked, where the product is used for its intended purpose requires a notification to the Swedish Medical Products Agency at least 30 days before the trial is going to start.
• is not CE marked or where the product is used outside its intended purpose of the CE marking requires an application to the Swedish Medical Products Agency.

If the device is a class I or non-invasive device in class IIa or IIb, a validation statement from the Swedish Medical Products Agency must be awaited.

If the device is a class IIa or IIb invasive device or a class III device, an approval from the Swedish Medical Products Agency is required.

You can find up-to-date and more detailed information on the approval procedures on the website of the Swedish Medical Products Agency.

If you are unsure whether your study needs approval, you can contact the Swedish Medical Products Agency for advice.

Notification and application, website of the Swedish Medical Products Agency External link.

Medical device studies abroad

If you plan to carry out studies on medical devices in other countries, you must make yourself informed about the current legislation in the relevant country. The European Clinical Research Infrastructure Network (ECRIN) has compiled information on regulatory requirements for many European countries. USA The Food and Drug Administration is the regulatory authority for medical devices in the United States and the China Food and Drug Administration is the Chinese equivalent, to name a few.

Compiled information on regulatory requirements for many European countries External link.

Medical device regulatory authority in the United States External link.

Medical device regulatory authority in China External link.

Adapted investigation plan needed for notification to the Swedish Medical Products Agency

If you are conducting a medical device clinical trial, you will need to adapt your research protocol. The research protocol for a clinical trial of a medical device is called a clinical investigation plan (CIP). The requirements for the content of a clinical trial plan are more extensive than the Ethical Review Authority's specification of what should be included in a research plan. The EU Medical Devices Regulation and ISO 14155:2020 provide detailed information on what to include.

An important part of the clinical investigation plan is the description of the data to be collected, the statistical considerations forming the basis of the study design, and how the data will be analysed. Other important elements are the description of the study population, the procedures that study participants are expected to undergo, how informed consent will be obtained, and a risk/benefit assessment with regard to study participation.

In addition to the clinical investigation plan, a number of other annexes must be included in the documents sent to the Swedish Medical Products Agency. Read more about this under Application.

Content for clinical research plan under the EU Medical Devices Regulation. External link.

Content for clinical research plan according to standard, ISO 14155:2020, SIS website. External link.

Information on the clinical investigation plan and annexes External link.

Designing a data collection tool

A medical device clinical trial must use a CRF, either in paper format or as an electronic system. The electronic CRF (e-CRF) can form the basis of a database created for analysis, while a paper CRF will need to be converted into electronic data at a later stage. Regardless of the format, a CRF is designed as a series of questions or checkboxes that study staff complete as the study participants answer questions or undergo various examinations that generate metrics. Data from the patient medical records can also be entered into a CRF. Annex C ISO 14155:2020 provides an example of what a CRF can contain.

If you use an e-CRF, there are specific requirements for the functionality and security of the system. For example, an e-CRF must have a so-called logging function to record who made any changes to the input data. The requirements for electronic systems in a medical device trial are set out in ISO 14155:2020. You must also take responsibility for how the electronic processing of sensitive personal data is conducted and you must know whether the electronic system means that personal data will be processed abroad or in a different facility than that of the entity responsible for research.

Keep in mind that all data collected in a CRF must be described in the clinical investigation plan, which must be approved by both the Ethical Review Authority and the Swedish Medical Products Agency. No other data may be collected.

Suggested content of CRF according to standard, ISO 14155:2020, SIS website. External link.

Assigning roles and responsibilities

In accordance with ISO 14155:2020, there are a number of roles with different responsibilities to be allocated when planning to conduct a medical device clinical trial.

Manufacturer

The Manufacturer is the entity responsible for the design, manufacture, labelling, instructions for use, packaging and indication of intended purpose of a medical device, and then placing the device on the market under their own name. The CE marking must be labelled by the manufacturer, regardless of who has carried out the manual production.

Sponsor

The sponsor is the individual or organisation responsible for initiating and conducting an approved clinical trial. It is common for the sponsorto also be the manufacturer of the medical device, but this is not a requirement.

The sponsor has overall responsibility for the conduct of the study and is responsible for, e.g.:

• planning and conducting the clinical study
• communication with regulatory authorities
• quality assurance and control
• potential subcontracting of work tasks and functions

The full description of the role and responsibilities of the sponsor can be found in ISO 14155:2020.

Principal investigator

The principal investigator is the person responsible for the conduct of a clinical study at a trial site. If the study is conducted at several trial sites, there should be one principal investigator at each site. The principal investigatorshall have documented training and experience within the field of application of the medical device. The need for the competence of the principal investigator must be assessed according to the application area of the product.

The full description of the role of the principal investigatorcan be found in ISO 14155:2020.

The tasks of the principal investigator charge include e.g.:

• lead the work on the study at the trial site
• ensure that informed consent is obtained from study participants according to the applicable rules and the clinical investigation plan
• ensure that the study is conducted according to the clinical investigation plan
• ensure that study participants receive the necessary medical care during and after the completion of the study
• carry out safety reporting
• ensure that reliable data is generated

The investigator has overall responsibility for the study at the trial sitebut may delegate tasks provided that the delegation is made in writing to a person with appropriate training and experience. A signature and delegation list should be established and updated if there are staff changes during the study. For a task to be carried out by a person other than the investigator, the task must first be delegated.

Monitor

The monitor is a person appointed by the sponsor who is responsible for independently verifying that the study is being conducted in accordance with the clinical investigation plan and other regulatory requirements. The monitor conducts the verification by visiting the trial sites participating in the study, reviewing the work and providing information on recommended actions to improve the study work. After the visit, the monitor writes a report to the sponsor.

In order for the monitor to supervise a study, in addition to having prior scientific and/or clinical knowledge, he or she needs to have knowledge of:

• ISO 14155:2020
• the product being tested and how it will be used
• the clinical investigation plan
• approved procedure for obtaining informed consent
• Sponsor procedures
• regulatory requirements

The full description of the role and responsibilities of the monitor can be found in ISO 14155:2020.

Collaboration between business, universities and healthcare

Clinical studies can be conducted on the initiative of healthcare professionals, but it is also common for a company or an academic researcher to come up with an idea for a new or modified medical device.

When the medical device industry and healthcare collaborate on the development of medical devices, for example by conducting a clinical study together, the collaboration rules must be followed.

Collaboration rules between healthcare and medical device industry External link.

When planning a clinical study in collaboration with the healthcare system, the sponsorshould be aware that specific roles with a certain type of expertise should be filled. Read more about roles and responsibilities in the paragraph above. In addition to the expertise that must be recruited to meet the requirements of ISO 14155:2020, the main rule is that the person named as the principal investigator in an ethics application must hold a doctorate.

For help in contacting clinics that may be interested in conducting your planned study, you can use the regional nodes' initiative on coordinated study requests External link..

Drawing up agreements and managing financial arrangements

If the clinical study is carried out as contract research, i.e. the study is initiated by an entity other than the healthcare system, an agreement must always be drawn up between the sponsor and the clinic or facility conducting the study. The agreement should address the division of responsibilities in the study and any financial arrangements. The healthcare entity often requires reimbursement for the additional costs that the study entails for the facility. Financial agreements for contract research must also be reported in the ethics application.

If the healthcare entity is the initiator of the clinical study, it is recommended that a written agreement between the researcher and the head of the facility is still made, for example on how additional costs for the clinic will be financed.

Additional agreements may need to be signed if, e.g., the study requires X-rays, pathology or a sample handling procedure via a central laboratory.

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.

Definition and purpose of performance studies according to the IVDR

The IVDR defines performance studies as studies conducted to establish or confirm the analytical or clinical performance of a product. The purpose of clinical performance studies is to establish or confirm aspects of product performance that cannot be determined by analytical performance studies, literature studies and/or previous experience with routine diagnostic testing.

The design of the clinical performance study

The sponsor shall perform a risk analysis before the start of the clinical performance study and risks identified shall be documented and written into the clinical performance study protocol.

The design of a performance study is based on the research question or hypothesis to be answered or tested. The study should be designed to ensure that the data collected are of good quality and can be used to answer the applicable research question. The research question and study design may vary depending on the purpose of the study.

Information on setting up a research question or hypothesis on the Idea page

Standard ISO20916:2019, SIS website External link.

Information on study design and statistical aspects

In addition to considering scientific aspects, there is a need to ensure that the design with best scientific approach is also ethically and practically feasible. It may also be useful to consider how the study design affects the quality of the data collected. A complex study design may require more training for users and staff or an extensive monitoring plan to avoid data quality issues compared to a design that largely follows normal healthcare procedures.

Informed consent

In addition to the requirements set by the Ethical Review Authority for the written information to be provided to the study participants, IVDR and ISO 20916:2019 provide specific recommendations on the information to be provided to participants in a clinical performance study.

Regarding insurance for study participants, there are also circumstances specific to performance studies. If the studies are carried out in the healthcare entity's facility, the patient insurance that the healthcare entity is obliged to have applies. However, there is no equivalent to Swedish Pharmaceutical Insurance for in vitro diagnostic medical devices.

EU regulation on in vitro diagnostic medical devices. External link.

Standard ISO 20916:2019, SIS website. External link.

Will the study be reviewed by the Swedish Medical Products Agency?

For interventional clinical performance studies and other performance studies involving risks to the subjects in the studies, the study must be reviewed by the Swedish Medical Products Agency.

Current and detailed information on the approval procedures, Swedish Medical Products Agency website. External link.

Application and notification information for clinical performance studies External link.

Writing a clinical performance study protocol

If you are going to conduct a clinical performance study of an in vitro diagnostic device, you must write a clinical performance study protocol (CPSP). This document shall include, e.g., a justification of the need for the performance study and a description of the objectives, design, methodology, monitoring, statistical considerations, organisation and implementation of the performance study. The IVDR and ISO 20916:2019 provide detailed information on what to include.

In addition to the clinical performance study protocol, a number of additional annexes according to Chapter I to Annex XIV of the IVDR should be included in the documents submitted to the Swedish Medical Products Agency.

EU regulation on in vitro diagnostic medical devices. External link.

ISO 20916:2019, SIS website. External link.

Designing a data collection tool

In an interventional clinical performance study and other performance studies involving risks to the subjects in the studies, there must be a CRF, either in paper format or as an electronic system. The electronic CRF (e-CRF) can form the basis of a database created for analysis, while a paper CRF will need to be converted into electronic data at a later stage. Regardless of the format, a CRF is designed as a series of questions or checkboxes that study staff complete as the study participants answer questions or undergo various examinations that generate metrics. Data from the patient medical records can also be entered into a CRF.

If you use an e-CRF, there are specific requirements for the functionality and security of the system. For example, an e-CRF must have a so-called logging function to record who made any changes to the input data. You must also take responsibility for how the electronic processing of sensitive personal data is conducted and you must know whether the electronic system means that personal data will be processed abroad or in a different facility than that of the entity responsible for research.

Keep in mind that all data collected in a CRF must be described in the clinical performance study protocol, which must be approved by both the Ethical Review Authority and the Swedish Medical Products Agency. No other data may be collected.

Assigning roles and responsibilities

In accordance with the IVDR and ISO 20916:2019, there are a number of roles with different responsibilities to be allocated when planning to conduct a clinical performance study.

The manufacturer is the person responsible for the design, manufacture, labelling, instructions for use, packaging and indication of intended purpose of an in vitro diagnostic medical device, and then placing the device on the market under their own name. The CE marking must be labelled by the manufacturer, regardless of who has carried out the manual production.

The sponsor is the individual or organisation responsible for initiating and conducting a clinical performance study. It is common for the sponsor to also be the manufacturer of the in vitro diagnostic device, but this is not a requirement.

The sponsor has overall responsibility for the conduct of the study and is responsible for, e.g.:

• planning and conducting the clinical study
• communication with regulatory authorities
• quality assurance and control
• potential subcontracting of work tasks and functions

The full description of the role and responsibility of the sponsor can be found in ISO 20916:2019.

The principal investigator is the person responsible for conducting a clinical performance study at a trial site. If the study is conducted at several trial sites, there should be one principal investigator at each site. The principal investigator shall have documented education and experience within the field of use of the in vitro diagnostic device. The need for the competence of the principal investigator must be assessed according to the application area of the product.

The full description of the role of the principal investigator can be found in ISO 20916:2019.

The tasks of the principal investigator charge include e.g.:

• lead the work on the study at the trial site
• ensure that informed consent is obtained from study participants according to the applicable rules and the clinical performance study protocol
• ensure that the study is conducted according to the clinical performance study protocol
• ensure that study participants receive the necessary medical care during and after the completion of the study
• carry out safety reporting
• ensure that reliable data is generated

The investigator has overall responsibility for the study at the trial sitebut may delegate tasks provided that the delegation is made in writing to a person with appropriate training and experience. A signature and delegation list should be established and updated if there are staff changes during the study. For a task to be carried out by a person other than the investigator, the task must first be delegated.

The monitor is a person appointed by the sponsor who is responsible for independently verifying that the study is being conducted in accordance with the clinical performance study protocol and other regulatory requirements. The monitor conducts the verification by visiting the trial sites participating in the study, reviewing the work and providing information on recommended actions to improve the study work. After the visit, the monitor writes a report to the sponsor.

In order for the monitor to supervise a study, in addition to having prior scientific and/or clinical knowledge, he or she needs to have knowledge of:

• ISO 20916:2019
• the product being tested and how it will be used
• the clinical performance study protocol
• approved procedure for obtaining informed consent
• Sponsor procedures
• regulatory requirements

The full description of the role and responsibilities of the monitor can be found in ISO 20916:2019.

Collaboration between business, universities and healthcare

Clinical studies can be conducted on the initiative of healthcare professionals, but it is also common for a company or an academic researcher to get the idea for a new or modified in vitro diagnostic medical device.

When the medical device industry and healthcare collaborate on the development of in vitro diagnostic devices, for example by conducting a clinical performance study together, the collaboration rules must be followed.

Collaboration rules between healthcare and medical device industry External link.

When planning a clinical performance study in collaboration with the healthcare system, the sponsor should be aware that specific roles with a certain type of expertise should be filled. Read more about roles and responsibilities in the paragraph above. In addition to the expertise that must be recruited to meet the requirements of ISO 20916:2019, the main rule is that the person named as the principal investigator in an ethics application must hold a doctorate.

For help in contacting clinics that may be interested in conducting your planned performance study, you can use Feasibility Sweden - a national study request service External link..

Drawing up agreements and managing financial arrangements

If the clinical performance study is conducted as contract research, i.e. the study is initiated by an entity other than the healthcare system, an agreement must always be drawn up between the sponsor and the clinic or facility carrying out the study. The agreement should address the division of responsibilities in the study and any financial arrangements. The healthcare entity often requires reimbursement for the additional costs that the study entails for the facility. Financial agreements for contract research must also be reported in the ethics application.

If the healthcare entity is the initiator of the clinical study, it is recommended that a written agreement between the researcher and the head of the facility is still made, for example on how additional costs for the clinic will be financed.

Additional agreements may need to be signed if, e.g., the study requires X-rays, pathology or a sample handling procedure via a central laboratory.

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.