June 23, 2021
Companion diagnostics (CDx) are a specific type of IVD, unfortunately not defined under the current European In Vitro Diagnostic Medical Device Directive (IVDD). The In-vitro Diagnostic Medical Devices Directive (IVDR) as well as ISO 20916, however, close this gap by defining CDx, and identify requirements for clinical performance (CP) studies with CDx.
What are companion diagnostics?
The new EU IVDR, whose date of application is May 26, 2022, defines in Article 2 (f) a ‘companion diagnostic’ as a device which is essential for the safe and effective use of a corresponding medicinal product to:
- identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or
- identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product.
IVDR recitals 10 to 12 provide further information on the CDx concept.
Requirements for CP studies with CDx
As mentioned in our previous blog post on ISO 20916, CP studies for a CDx in which test results obtained during the study are used for patient management decisions and used to guide treatments are considered interventional clinical performances studies.
According to normative Annex A of ISO 20916, these interventional studies are studies for which additional general requirements apply:
- Clinical Performance Study Protocol (CPSP),
- An Investigator’s brochure (IB),
- An Informed Consent (ICF) and
- Other essential study documents specified in Annex H need to be established.
Ethics committee approval as well as national competent authority approval will need to be obtained in many EU member states. Therefore, compliance to ISO 20916 requirements should be considered to verify that the rights, safety, dignity and well-being of the study participants are protected, and that the data generated are scientifically valid, reliable and robust. Another important aspect is the establishment of proper IVD safety event documentation and reporting. Finally, a Clinical Performance Study Report (CPSR) needs to be generated.
Challenges for CP studies with companion diagnostics
The CDx manufacturer and the investigational medicinal product manufacturer are quite often separate companies, and roles and responsibilities for the planned study are not clearly contractually defined between these two companies. Studies with CDx are usually driven by the pharmaceutical company, and the CDx manufacturer often plays only a supporting role in the set-up and execution of the study. Medicinal product studies with CDx are then conducted according to general and national medicinal product regulations and requirements.
Often there is a certain unawareness of the applicability of ISO 20916 for CP studies with a CDx at pharmaceutical companies or involved partners (e.g., CROs) since this standard is not referenced in the current IVDD. In addition, national legislative requirements for CP studies, which need to be met, are often hard to identify (national regulations are frequently written in national language only). Furthermore, the written procedures of CDx manufacturers and involved pharmaceutical companies might not adequately address CP study processes.
Overall medicinal product study requirements and CP study requirements need to be addressed.
Considerations for CP studies with CDx
- Along with requirements for medicinal product studies, all involved parties need to understand and follow national legislations applicable for CP studies with CDx.
- Define roles and responsibilities for the studies between pharmaceutical company and CDx manufacturer.
- Consider ALL applicable ISO 20916 aspects for the development of the essential study documents. Two study protocols might be expected, but if only one protocol is written, ensure that the study protocol identifies the device involved as an investigational IVD, and that required IVD CP study-specific elements are included. The same applies for other essential study documents. An additional IB needs to be generated for the companion diagnostic.
- Ensure that study site personnel are qualified to conduct CP studies and trained in the respective requirements as requested by the National Competent Authority (NCA) and Ethics Committees (EC).
- Set up appropriate safety recording and reporting process(es) defining who will be responsible for recording and reporting of safety events, as well as when to report according to the medicinal product regulations and when according to IVD regulations (e.g., safety events due to the sample taking). Reach out to the NCA for guidance, if needed.
- Ensure that all required EC and NCA study approvals for the medicinal product and the CDx study part are obtained. Please note that CP study approvals from ECs must be obtained for ALL study sites involved in medicinal product studies with CDx, even if the samples are shipped outside of the respective country for analysis.
- Review your written processes to close eventual gaps (processes for medicinal product studies are not that different from those for CP studies).
We recently have seen increased scrutiny by ECs and NCAs when it comes to studies with CDx. Clinical evidence collected in current and previous non-compliant studies will likely not be accepted for the required demonstration of clinical performance under the IVDR (CE Marking) as well as for the marketing authorization application for the involved medicinal product.
Complete re-dos of CDx studies for re-certification under IVDR for the CDx and the medicinal product as well as Field Safety Corrective Actions (FSCA) or even recalls could then become realistic scenarios. To avoid this, manufacturers should proactively reassess older CP study data to determine whether they have met the general study criteria. Identified gaps should carefully be discussed, and further studies such as Post Market Performance Follow-ups (PMPF) may need to be initiated to support current clinical claims and to provide supportive information and evidence for clinical performance to Notified Bodies. Even a well-structured PMPF plan might reduce the risk of a CE Mark suspension.
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
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