Clearing the Maze Navigating Clinical Performance Studies in the Absence of EUDAMED

IVD clinical performance studies (CPS) are a necessary component to demonstrate the safety and performance of IVD devices. Manufacturers may determine that a CPS is needed to support the conformity assessment of the device. While clinical performance studies are not new, Regulation 2017/746 outlines new requirements for such studies, and manufacturers may now be determining that a CPS is necessary to support the conformity assessment of the device. 
IVDR outlines the coordinated EU Member State Competent Authority (CA) assessment procedure and application process for CPS applications facilitated by the EUDAMED system. When EUDAMED is active, study sponsors may submit a performance study in a single application to be transmitted electronically to all EU CAs. Article 74 lays the groundwork for the assignment of a single member states to review the application. 

However, in the absence of EUDAMED, sponsors are responsible for submitting CPS applications to each EU CA where the study will be conducted. This process requires careful planning as member states differ in their implementation of Regulation 2017/746 clinical performance study reviews. In fact, the differences in application processes across EU member states is causing delays to clinical studies and, in some cases, preventing EU patients from accessing precision medicine clinical trials. This article will help Sponsors navigate the maze of CPS studies in the absence of EUDAMED, ensuring efficient application processes. 

What studies require an application for authorization by Member State CAs? 
Depending on the study design and the status of the device used in the study, some studies may require explicit CA authorization; others may only require a notification of the study to the CA, and some may require neither.  

If a manufacturer determines a CPS is necessary, the CPS must be designed and conform to Annex XIII, Annex XIV (if applicable), and Chapter VI of Regulation (EU) 2017/746. If clinical studies pose additional risks to subjects or are interventional by design, they are subject to additional requirements, including CPS authorization from CAs in the countries where the study is to be performed. While this article focuses on applications for authorization, certain studies, based on their low-risk design, may only require the sponsor to notify the CA of the study rather than having the application reviewed for explicit authorization. 

Many CAs have provided resources for sponsors to help evaluate the risk associated with the study and whether an application for authorization is required for the study. Sponsors must use their device risk evaluations and occasionally consult with CAs to determine if their study falls into a category of additional risk. Study sponsors should be acutely aware of the local regulations that may mean their study must be authorized by CAs prior to initiation.  

What is needed in a CPS application for authorization? 
The requirements of a CPS application are stated in Annex XIV Chapter I. Information to be submitted to the CAs includes the following:  

• Study Application Form
• Investigator's Brochure
• Performance Study Plan (must be drafted according to Annex XIII Section 2 and 3)
• Other Information
  • Signed statement that the device conforms to the general safety and performance requirements in Annex 1 and that every precaution has been taken to protect the health and safety of the subject.
  • Proof of insurance cover or indemnification of subjects in case of injury
  • Documents to obtain informed consent (including patient information sheet and informed consent document).
  • Description of arrangements to comply with applicable rules on the protection and confidentiality of personal data
  • If requested, full details of the available technical documentation (such as risk analysis and management) 

The requirements for the application form are outlined in Annex XIV. However, in December 2022, the MDCG released the MDCG 2022-19 Performance Study application and notification documents, which contain application templates and checklists of documents to be submitted to the competent authorities. Note that not all CAs are using this form. Some countries may have additional local requirements or submission portals and require country-specific application forms.

While the content to be submitted to CAs is stated in IVDR, the overall submission process and required content continue to vary by CA. Sponsors should keep the following points in mind when planning their CPS authorization applications. 

Submission Content 
Informed Consent documents and subject recruitment materials must be provided in the member state's national language. Whether the remaining application must be translated into the national language varies by member state. Some documents, such as proof of insurance or study summaries, may be required in the national language. Most often, the application may be submitted in English, or countries may have dual-language application forms and only require a subset of documents in the national language. 
Most CAs have fees for authorization and notification and application modifications after authorization. Note that if an application fails validation or is not authorized (the application does not meet IVDR CPS requirements), Sponsors may be required to submit a new application with a new review fee. 

Submission Timelines 
Per Regulation (EU) 2017/746, a positive ethical committee decision must be shared with the CA. The ethical committee review process varies by CA. 

Some member states have consolidated the ethical committee process into the application for authorization. In these cases, when an application is submitted to the CA, the application is forwarded to the appropriate ethical committee for simultaneous review. Other member states require study sponsors to seek and obtain ethical committee review and approval prior to submitting the CPS for CA review. Some member states require that the CPS application be submitted separately to the ethical committee and CA on the same date to be reviewed separately. And other member states allow sponsors to submit the CPS application to the CA while the ethical committee review is separately ongoing, in parallel. 

Sponsors must be acutely aware of these differences to understand how the ethical committee review and process will affect the overall study timeline. 

Submission Format 
Additionally, submission methods vary widely by member states. Some countries use country-specific electronic portals. Others require submissions by email or even post mail. Sponsors should check with each member state to determine the administrative requirements for submission. Member states may have strict requirements for naming files, appendices, and organizing documents, and not appropriately meeting these requirements can delay validation and overall review of the application.  

Summary
Certain studies are subject to CA authorization. The requirements for authorization are outlined in Chapter VI, Article 58, and Article 70. Application requirements and timelines for application review are noted in Regulation (EU) 2017/746. However, in the absence of EUDAMED, sponsors must be acutely aware of how to submit an application to each EU CA and the procedural differences to complete the authorization process most efficiently. 

These authorizations are intended to protect subjects and users and assist the study sponsor in properly documenting clinical performance evidence. Foresight and preparation can make the difference between getting lost in the maze of the requirements and clearly navigating the way.