CP studies: Planning
To ensure the CP study is planned and conducted adequately, a clinical performance study protocol (clinical performance study plan in the IVDR) (CPSP) should be generated. Topics usually included are described in ISO 20916 section 5.5.3 and normative Annex B, and include information on:
- Sponsor
- Study IVD (and comparator, if applicable) and intended use
- Specimens and when applicable, subjects providing specimens
- Objectives and endpoints (primary and secondary)
- Procedure involved
- Informed consent process
- Statistical consideration
- Monitoring and data management
- Adverse event, adverse device effects and device deficiency documentation and reporting
Note: Much of the required information can be documented separately from the CPSP (e.g., information on study sites or SAE reporting), but should be very carefully addressed. Often these documents need to be included in respective country submissions as well as notifications to ECs and NCAs.
Other activities and documents needed during the set-up of the CP study are:
- Risk evaluation to assess the risk associated with participation
- Site selection (selection, assessment and qualification of study staff and study sites),
- Monitoring plan,
- Case report forms,
- Contracts (with all involved parties).
- Labelling
- Good Clinical Practice (GCP) study documentation (Annex H)
Note: Additional factors, such as the current coronavirus pandemic, and their potential impact on these activities need to be considered when planning and conducting CP studies.
CP studies: Conduct
The CP study can only be started after written approval or favorable opinion from the involved EC and where applicable, approval from the respective NCA.
Site initiation: Prior to full initiation of the involved study sites, it will be ensured that required study site documentation is in place, including signed contract(s) and respective approval(s). The IVD device needs to be available at the study site. In addition, it will be confirmed that the study sites are trained on general study requirements (e.g., study site personnel responsibilities ) and specific CP study requirements (e.g., the CPSP and the use of the IVD).
Site monitoring: Once the CP study sites begin enrolling participants monitoring will be conducted to verify that the study is conducted in accordance to the CPSP, ISO 20916 and any other applicable requirements. During routine monitoring it will be verified, among other issues, that:
- The IVD is used according to CPSP or instructions for use ;
- The IVD is available and IVD accountability is performed accurately;
- Study records are correct, complete and up to date;
- Safety documenting and SAE reporting is done appropriately to country legislation; and:
- Data protection regulations such as the General Data Protection Regulation (GDPR) are respected.
Activities conducted as well as findings and observations will be documented in a monitoring report (see ISO 20916 Section 7.3.3).
CP study – Close Out
Close out activities will be conducted for each study site to ensure that the site records are complete; all sponsor records are retrieved; remaining IVD products are returned or destroyed; issues have been resolved; and relevant parties were informed about the end of the study.
A Clinical Performance Study Report (CPSR) will be generated for every CP study. The expected content of a CPSR is outlined in ISO 20916 section 8.2. The results section, for example, will include information on the statistical analysis used; performance and safety results; plus provide an accounting of all subjects and specimens; and a discussion as well as overall conclusion on the outcome of the study.
Normative Annex D provides further guidance for generation of the CPSR for certain CP (higher risk) studies.
Note: Many additional topics such as document retention, premature study termination and auditing are also addressed by ISO 20916.
Conclusion
The amount of tasks to be considered for CP studies is immense, and it is essential that experienced and trained personnel with a proficient understanding of their roles and responsibilities are involved in the planning and conduct of these studies. In addition, CP studies need to be budgeted accordingly. The ISO 20916-compliant conduct of CP studies might be considered as extra burden by the manufacturer; it will however, result in robust clinical performance data, easier demonstration of clinical evidence and potentially faster approval processes under the European IVDR.
Part Three of our series on IVD clinical performance study requirements will focus on companion diagnostics. Part One of our series examined the differences in requirements between performance evaluation studies under the IVDD and clinical performance studies under the IVDR.
Dietmar Falke is Head of Clinical Research and Oliver Eikenberg is Senior Consultant RA/QA at Emergo by UL.
Additional European IVD regulatory resources from Emergo by UL
- EU IVDR compliance preparation and resource center
- European Authorized Representative for clinical trials in-country representation
- Whitepaper: EU IVDR conformity assessment options for IVD devices