FAQ's

Not all. An IVD used in a clinical trial needs to be compliant with the in vitro diagnostic medical device legislation. This implies that the IVD either has the CE marking for the intended purpose, or is an in-house IVD (see Q3) or is a device for a performance study according to the IVDR ongoing in parallel (see Q6, Q7). In-house IVDs and devices for performance study are not required to bear CE-marking

Yes. This remains possible.

With the exception of the relevant general safety and performance requirements set out in Annex I, the requirements of the IVDR shall not apply to devices manufactured and used only within health institutions established in the Union, provided that all of the conditions of Article 5(5) are met.

In-house IVDs might also be regulated in national legislation and it is necessary to check with the national competent authorities responsible for performance studies, which requirements apply.

No, not all assays, but those that fulfil the definition of an IVD are subject to the IVD legislation. Such assays may have a medical purpose within the clinical trial, e.g. when they guide medical management decisions or follow-up (see Q6).

The IVD Directive 98/79/EC and the IVDR lay down rules concerning the placing on the market, making available on the market or putting into service of IVD for human use and accessories for such devices in the European Union. In addition, the IVDR lays down rules specific to devices for performance studies and in-house devices.

An assay is considered an IVD if the manufacturer assigns an intended purpose that fulfils the definition of an IVD according to IVDR Article 2 (see Q6). Where a clinical trial sponsor assigns a medical purpose to an assay in the context of the clinical trial in a way that the assay fulfils the definition of an IVD according to IVD Regulation 2017/746 Article 2, the clinical trial sponsor may assume the role of a manufacturer under the IVDR3 . In this role, it is up to the clinical trial sponsor to determine the regulatory status of the assay based on the planned use in the clinical trial. In case of doubt, consultation of the respective NCAs for IVDs and for clinical trials (with medicinal products) is recommended.

Some examples include assays providing information for clinical trial related medical management decisions (typically to select patients for enrolment in the trial, assign patients to a treatment arm, etc.) and/or may be used to guide follow up measures during and beyond the clinical trial. This would, for example, not be the case, in settings where all trial participants are tested irrespective of treatment arm or medical management and the analysis of impact is conducted retrospectively and where medical management is not impacted by assay results.

Figure 1 visualises, as an example, the flow of a blinded clinical trial with two treatment arms, where the key processes for which assays might be utilised are highlighted. The processes in blue are considered to be used for medical management decisions of trial subjects. These include assays used for inclusion and exclusion of subjects, treatment allocation as well as monitoring the safety and efficacy of the treatment during the trial.

The processes in pink are likely not to impact the medical management of the trial subjects. These include stratification and endpoint analysis or other exploratory assays for which correlation with clinical parameters is investigated retrospectively without impact on patient treatment (medical purpose). In relation to endpoints, it is important to acknowledge that these assays may be considered IVDs in future clinical trials (e.g. used for allocation or monitoring). Where this development is predictable, the assay should be developed and validated in compliance with the applicable requirements of Annex I of the IVDR as an IVD from the beginning. Importantly, in most cases, the assay will also be utilised during the trial as part of the monitoring of the trial subjects, which implies need for compliance with IVDR requirements.

Fig. 1 Simplified examples of use of assays on human samples in a clinical trial. Assays marked in blue (diamonds) are considered to be assays which will likely be considered IVDs as they are used for medical management decisions of trial subjects within the trial. The processes in yellow pink (ellipses) are considered to likely not to impact the medical management of the trial subjects and therefore would not have a medical purpose in the trial.

Note that using a CE marked IVD outside its prescribed intended purpose is not covered by the CE marking provided to that device and renders it a non-CE marked IVD in the context of this clinical trial.

Where a non-CE marked IVD is used for a medical purpose in a clinical trial the IVD must either be

• a device for performance study (it is not acceptable to use an investigational IVD without evaluating its performance), or
• an in-house IVD (see also Q3).

If a non-CE marked assay is used for a medical purpose in a way that the assay fulfils the definition of an IVD according to Article 2 of the IVDR, outside of the abovementioned settings, this is not compliant with the IVDR. It is the responsibility of the clinical trial sponsor to ensure compliance with relevant provisions of Union and national law, including the IVDR.

If performance data is generated for an IVD outside of a performance study it might be insufficient for a future performance evaluation, and thus further studies might be required to generate sufficient clinical evidence.

No. Where an assay, instrument, apparatus, appliance material or other article, including software is intended for research use only and is assigned a medical purpose by the clinical trial sponsor in the clinical trial protocol in a way that the assay fulfils the definition of an IVD according to IVDR Article 2, it becomes an IVD and can no longer be considered a research use only assay. It becomes regulated under the IVDR (see Q4-Q6).

In-house devices can be used as long as the provisions of the IVDR and relevant national legislations are satisfied, which include notably, that the device must be manufactured and used within a health institution established in the EU and the device is not transferred to another legal entity. In-house IVD must fulfil relevant general safety and performance requirements set out in Annex I.

Samples can travel and be analysed by means of in-house devices based in a different location than the trial site facilitating a core lab facility approach. The in-house concept applies to the device itself, which must be manufactured and used within the responsible health institution.

No, there is no dedicated procedure foreseen in the Regulations and therefore, currently, no harmonized procedure is in place. However, where a single combined trial will serve as the clinical performance study for the device and the clinical trial of the medicinal product, the study documentation required for submissions (if applicable) may be partially overlapping. Not all clinical performance studies have to be submitted to the regulatory authorities (see Q14). Sponsors of these clinical trials are encouraged to consult national guidance documents and contact National Competent Authorities prior to clinical trial submission.

Only those IVDs should be mentioned in the cover letter that are specifically required by the protocol to be used to achieve the objectives of the clinical trial. The information provided should permit identification of the IVD being used and whether it is CE-marked for the planned use. Evidence of CE-marking generally does not have to be provided in the CTA, but it is the responsibility of the clinical trial sponsor to determine whether the device is used in the clinical trial in line with the manufacturer’s intended purpose.