Performance studies of IVD devices

Performance studies started before 26 May 2022

Performance studies started before 26 May 2022 and conducted in accordance with the previous regulatory framework (LVFS 2001:7 based on the IVDD), may continue to be conducted also after the IVDR date of application.

Sponsor does not have to submit an application or notification to the Swedish Medical Products Agency (MPA) for such ongoing performance studies when the IVDR starts to apply on 26 May 2022. However, it is necessary to ensure that other applicable permissions have been obtained for the study prior to study start, such as ethical approval and biobank agreement, in those situations where it is required by other legislation.

Performance studies from 26 May 2022

For performance studies started from 26 May 2022, the IVDR applies.

The IVDR defines a performance study as a study undertaken to establish or confirm the analytical or clinical performance of a device.

The purpose of clinical performance studies is to establish or confirm aspects of device performance which cannot be determined by analytical performance studies, literature and/or previous experience gained by routine diagnostic testing.

The provisions on clinical performance studies are located in chapter VI and Annexes XIII and XIV of the regulation.

General requirements for performance studies

The manufacturer must ensure that a device intended for performance studies meets the general safety and performance requirements set out in Annex I to IVDR, except for the aspects covered by the performance study. The manufacturer must also ensure that all precautions have been taken with regard to these aspects to protect the health and safety of patients, users and others. Performance studies should, where appropriate, be performed under conditions that correspond to the normal conditions of the intended use of the device.

Clinical performance studies shall be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in such performance studies are protected and prevail over all other interests and the data generated are scientifically valid, reliable and robust.

Performance studies, including performance studies where residual test material is used, must be carried out in accordance with the legislation that applies to the protection of personal data, which means that provisions in the Data Protection Regulation (GDPR), the Biobanks Act and laws on ethical review of research may need to be considered.

Good study practice

The studies shall be conducted according to a clinical performance study plan and shall be designed in such a way as to maximize the relevance of the data while minimising potential bias.

Performance studies should be conducted in accordance with Good Study Practice (GSP), which is described in the international standard ISO 20916 In vitro diagnostic medical devices – Clinical performance studies using specimens from human subjects – Good study practice.

Additional requirements for certain performance studies

The IVDR introduces requirements for sponsors to apply for authorisation or notify the Swedish MPA when it comes to certain types of performance studies. More information on this topic is available in the next section.

However, many performance studies will also in the future be possible to conduct without submitting an application or notification to the Swedish MPA.

Note that according to IVDR, the sponsor must send its applications and notifications, safety reports and other reporting regarding performance studies of medical devices for in vitro diagnostics to the authorities via the European database European Database on Medical Devices (EUDAMED). However, this functionality in EUDAMED is not yet available and therefore are applications and notifications etcetera for clinical investigations and performance studies are handled nationally until further notice.

In Sweden, all documentation must be sent to the Swedish MPA.

When is an application required?

From 26 May 2022 must an application be submitted to the Swedish MPA if the performance study:

1. Involves surgically invasive sample-taking which is done only for the purpose of the performance study.
2. Is an interventional study of clinical performance, which in the IVDR means that the test results may influence patient management decisions and/or may be used to guide treatment.
   Note that the term interventional study has a different meaning in the context of clinical trial legislation for medicinal products.
3. Involves additional invasive procedures or other risks for the study subjects, even if these are not related to the sample collection.
4. Involves companion diagnostics and when not only left‍-‍over samples are used.

This follows from Articles 58.1 and 58.2 of the IVDR.

When is a notification required?

From 26 May 2022 must a notification be submitted to the Swedish MPA if the performance study:

1. Investigates companion diagnostics using left‍-‍over samples rather than samples collected specifically for the conduct of the performance study (see Article 58.2 of the IVDR).
2. Is assessing an already CE‍-‍marked device, within the scope of its intended purpose, and involves submitting subjects to procedures additional to those performed under the normal conditions of use of the device, and those additional procedures are invasive or burdensome (see Article 70.1 of the IVDR).

Processing of application and notification

Substantial modifications

Substantial modifications must be submitted to the Swedish MPA and will also be assessed by the Swedish Ethical Review Authority. The sponsor needs to wait 38 calendar days after the notification before the modification is implemented unless the approval letter is issued earlier.

Sponsor

The company, individual, institution or organisation which takes responsibility for the initiation, management and setting up of the financing of the performance study, is called sponsor.

Among other things, the sponsor shall:

• make sure all documentation about the performance study and in vitro diagnostic medical device is available for the competent national authorities before, during and after the study
• obtain all necessary authorisation
• have an agreement with the investigators in place to ensure that any serious adverse events and product deficiencies that could have caused serious adverse events, are reported by the investigators to the sponsor
• make sure the study is conducted according to current clinical performance study plan and good study practice
• produce a performance study report and its results.

Investigator

An individual responsible for the conduct of a performance study at a performance study site is called an investigator.

Subject

An individual who participates in a performance study and whose specimen(s) undergo in vitro examination by a device for performance study and/or by a device used for control purposes is called a subject. It is important that the subject participates voluntarily, and that the investigator has provided the subject with information about the study and the foreseen risks before the subject consents to participate. In exceptional cases a legal representative may be designated to provide consent on behalf of the subject.

Devices intended for performance studies

The devices tested in a performance study must meet the general safety and performance requirements set out in Annex I to IVDR, with the exception of the aspects covered by the performance study. In addition, all necessary precautions must be taken to protect the health and safety of the subjects.

It is the natural or legal person responsible for the manufacturing of the in vitro diagnostic medical device who is required to have documentation on the safety and performance of the device, and who must certify that the device meets the relevant general requirements of Annex I to IVDR, even if the sponsor of the performance study is not the manufacturer of the device.

If a sponsor makes any changes to a device, such as relabelling or additional labelling, the sponsor needs to ensure that the devices continue to meet the relevant requirements.

A manufacturer or sponsor who uses a subcontractor to handle devices in performance studies should therefore have an agreement with the subcontractor and appropriately ensure that the subcontractor complies with the quality requirements of the manufacturer or sponsor.

Template for declaration of conformity

Notification during the ongoing study

Serious adverse events, substantial modifications and other updates made during the study must be reported or notified to the Swedish MPA. The MPA must also be notified when the performance study is completed or temporarily halted.

Control of performance studies

The Swedish MPA performs surveillance of performance studies of in vitro diagnostic medical devices in Sweden. This means that the agency reviews that the studies are conducted according to applicable laws and regulations. As part of the MPA surveillance activities, inspections may be performed, mainly at participating study sites. Surveillance may also be performed as in‍-‍depth review of the performance study documentation.

If the Swedish MPA considers that the regulatory requirements are not fulfilled, the MPA may interfere and require that the sponsor amends the study.

The Swedish MPA may also recall the authorisation for a performance study, require that the investigation is temporarily halted or stopped permanently.