Regarding IVDs that are currently on the market on the basis of Directive 98/79/EC, do they need to undergo conformity assessment under the IVDR to remain on the market under that Regulation?
The IVDR does not foresee a recognition of Directive marketed IVDs but lays down various transitional provisions for IVDs compliant with Directive 98/79/EC. For more details on transitional provisions see the EU Commission website.
Do all IVDs used in a clinical trial require CE marking at the time of the clinical trial?
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
Can I use an in-house IVD in a clinical trial?
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.
Are all assays used in a clinical trial subject to the IVD legislation?
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.
When does an assay used on human samples qualify as an IVD in a clinical trial?
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.
What are examples of assays used in clinical trials which are IVDs?
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.
In which situations may a non-CE marked IVD (or an IVD that is CE marked for another intended purpose) be used in a clinical trial for a medical purpose according to the IVDR?
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.
Is a use in research sufficient justification for an assay to be defined as Research Use Only?
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).
Can an EU core lab facility4 that is part of a health institution established in the Union and has developed an in-house IVD receive samples from several clinical trial sites for analysis, or does the in-house IVD device have to be co-located with the clinical trial site?
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.
Is there a common EU procedure for combined trials?
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.
Which IVDs should be listed in the cover letter of the clinical trial application?
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.
Which information needs to be provided in the clinical trial application6 , if an assay with medical purpose that qualifies as an IVD is used in a clinical trial where the assay does not have a CE marking for the intended purpose (including in-house assays)?
According to Annex I.B.7 (i) of the CTR, the clinical trial sponsor shall include in the Cover letter the list of medical devices which are to be investigated in the clinical trial but which are not part of the investigational medicinal product or products, together with a statement as to whether the medical devices are CE-marked for the intended purpose. This should be understood to refer to medical devices (including IVDs) which are specifically required by the protocol to be used to achieve the objectives of the trial.
Use of an IVD in a clinical trial may meet the definition of a device for performance study. (See glossary ‘device for performance study’ and ‘performance study’)
For each device used in the clinical trial that meets the definition of a device for performance study, the sponsor of the clinical trial should comment on the need for notification or application for the clinical performance study conducted in parallel with the clinical trial, based on the applicable IVD legislation. Reference should be made to EUDAMED Single Identification Number (SIN) and/or National Competent Authority reference numbers (if available) for planned or submitted performance studies. To facilitate bridging between clinical trial and performance study, the IVD being used should be identified in the cover letter and protocol of the clinical trial.
Where the IVD manufacturer is supporting the clinical trial, which is also a performance study, the clinical trial sponsor should obtain a statement from the IVD manufacturer that the device for performance study in question conforms to the general safety and performance requirements laid down in Annex I of the IVDR, apart from the aspects covered by the clinical performance study and that, with regards to those aspects, every precaution has been taken to protect the health and safety of the subject.
Where the clinical trial sponsor is also the manufacturer of the IVD or assumes the role as manufacturer of the IVD according to Article 16 IVDR, the clinical trial sponsor must draw up their own statement as above. In case the study falls under IVDR Art 58 (1) or (2), it must be designed, authorised, conducted, recorded and reported in accordance with IVDR Art. 58-77 and Annex XIV.
In the CTA cover letter, the availability of this statement should be confirmed, and the aspects that are covered in performance study as part of the clinical trial should be listed. The statement is to be kept with the sponsor’s trial master file (TMF) and investigators’ site file (ISF) and made available for inspections or at the request of NCAs.
In case of confidential information in the description of the performance studies, a redacted cover letter can be submitted, as necessary.
In addition, further details on compliance with IVDR and Annex I of the IVDR can be provided in the protocol, according to CTR Annex I 17. a)-f).
Which information needs to be provided in the clinical trial application for an in-house IVD?
In principle, in the case of in-house IVDs, the sponsor should provide the name of the health institution where the IVD is manufactured and used and a link to their IVDR Art 5(f) declaration. It is recommended to document this aspect in the harmonised template document.
The IVD analysis must be carried out in a laboratory complying with ISO15189, or, where applicable, with national provisions, in line with IVDR Article 5(5)(c).
In addition, further details on compliance with IVDR Article 5(5) and Annex I of the IVDR can be provided in the protocol, according to CTR Annex I 17. a)-f).
Please note that Regulation (EU) 2022/112 amends the IVDR to defer the application of certain conditions for in-house devices.
What are the notification/application requirements for the performance study according to the IVDR?
Where the performance study is either an interventional clinical performance study or involves risks for the subjects of the study an application is necessary. Additional reporting and documentation obligations apply according to Art. 58 (1) and (2) IVDR.
Where the IVD is being used according to its intended purpose outlined in the instructions for use, Article 70 may apply. The submission requirements from the IVDR perspective will depend on the particulars of the device in question and the design of the performance study (Article 57, 58 and 70 IVDR).
What are the respective responsibilities of the clinical trial sponsor and IVD manufacturer including in the case of co-development and use in a combined trial?
Clinical trial sponsor requirements are defined in Article 2.2.14 CTR: The sponsor is responsible for the initiation and management of the clinical trial, including the selection and use of IVDs. The sponsor is responsible for the overall compliance of products used in the clinical trial with the CTR and other relevant EU and National legislation. Clinical trial sponsors are reminded of their obligations according to ICH-GCP E6 (R2) to document the competence of a laboratory to perform a certain test to support the reliability of results. This information should be kept at the sponsor’s Trial Master File (TMF) and, when applicable, at the investigator’s site file. Site suitability in accordance with Art 50 and Annex I N67 of the CTR should be documented. As good practice recommendation, this should take place by using the harmonised template document.
In case of a clinical trial where the IVD is used outside its intended purpose the clinical trial sponsor assumes the obligations incumbent on manufacturers according to Article 16(1) of the IVDR.
It is the intended purpose, which determines the applicability of the IVDR for an assay and not the intention (or not) of obtaining a CE-mark at a later stage. Where the assay qualifies as an IVD under the IVDR a natural or legal person needs to take responsibility for the safety and performance of the IVD device.
In situations where it is procedurally feasible and where the same ethics committee is responsible for evaluating the clinical trial AND performance study aspects of a combined trial – Would there be a legal requirement for two separate ethics opinions, or could the outcome be a single document for both aspects?
According to IVDR Art. 2 (59) and Art 58 (3), and CTR Art. 2.2.11, recital (18) and Art. 4, the ethics committees operate according to national law. It is up to the Member States to organize the work of the ethics committees and it is up to the Member States to ensure that the procedures for the review by the ethics committees are compatible with the clinical trial or conformity assessment procedures in the CTR and IVDR respectively. However, in situations where it is procedurally feasible and where the same ethics committee is responsible for evaluating the clinical trial and performance evaluation aspects of a combined trial, there is no legal requirement for two separate ethics opinions. The outcome could be a single document for both aspects, provided this is permissible under national law of the member state.
At the same time, in accordance with Art 9 of the CTR, Member States shall ensure that the persons validating and assessing the application do not have conflicts of interest, are independent of the sponsor, of the clinical trial site and the investigators involved and of persons financing the clinical trial, as well as free of any other undue influence. Member States shall ensure that persons admitting and assessing the application have no financial or personal interests, which could affect their impartiality.