Roberta Carbone, Chief Scientific Officer of Tethis S.p.A.
I had the pleasure of speaking to Roberta Carbone, Chief Scientific Officer of Tethis S.p.A. Roberta attained a Ph.D. in Forensic Medicine at University of Genoa; after two years at NIH, Bethesda (US), she worked as Assistant Researcher at EIO in Milan (Italy), focusing on technological innovation in oncology. She is author of more than 30 publications and several patent applications. She joined Tethis S.p.A in March 2006 where she currently is the CSO, working on innovative diagnostics in oncology, based on Tethis proprietary nanomaterials.
What are the key challenges involved in the successful introduction of a liquid biopsy test into the clinical market? How does the new IVDR affect the introduction of liquid biopsy tests into the clinical routine in the EU market?
Despite the evident advantages of liquid biopsy tests compared to the conventional tissue biopsy, there are just few relevant examples of liquid biopsy assays introduced in the market: looking at these examples, mainly based on ctDNA detection (such as cobas EGFR, Guardant360 CDx or FoundationOne Liquid CDx), it appeared that clinical utility and process standardization are the main key elements that can drive the introduction of a new test in clinics. However, for the full introduction in clinical routine diagnostics, the cost of the test should be considered, and still is a key challenge to be addressed, except only for those assays targeting few mutations. However, the new IVDR, that for some aspects is still lacking clarity, will require an extensive validation of all the elements of the flow composing the assay, including for instance the software for analysis that in the new regulation is considered as a “Medical Device per se” if its utilization is providing clinical information to the patient status. This is a dramatic difference compared to the previous IVDD and it is expected to strongly impact, limit or delay the implementation and introduction in the clinic of many diagnostic assays including liquid biopsy tests. Moreover, LDT assays, which so far have been developed in the context of liquid biopsy, will be incorporated within the IVDR specifications of “in vitro medical device” used for diagnostics, impeding their utilization in the market without proper validation. Therefore, a strong effort from companies will be required to accomplish the new IVDR.
What are the key challenges involved in the successful introduction of a liquid biopsy test into the clinical market? How does the new IVDR affect the introduction of liquid biopsy tests into the clinical routine in the EU market?
Despite the evident advantages of liquid biopsy tests compared to the conventional tissue biopsy, there are just few relevant examples of liquid biopsy assays introduced in the market: looking at these examples, mainly based on ctDNA detection (such as cobas EGFR, Guardant360 CDx or FoundationOne Liquid CDx), it appeared that clinical utility and process standardization are the main key elements that can drive the introduction of a new test in clinics. However, for the full introduction in clinical routine diagnostics, the cost of the test should be considered, and still is a key challenge to be addressed, except only for those assays targeting few mutations. However, the new IVDR, that for some aspects is still lacking clarity, will require an extensive validation of all the elements of the flow composing the assay, including for instance the software for analysis that in the new regulation is considered as a “Medical Device per se” if its utilization is providing clinical information to the patient status. This is a dramatic difference compared to the previous IVDD and it is expected to strongly impact, limit or delay the implementation and introduction in the clinic of many diagnostic assays including liquid biopsy tests. Moreover, LDT assays, which so far have been developed in the context of liquid biopsy, will be incorporated within the IVDR specifications of “in vitro medical device” used for diagnostics, impeding their utilization in the market without proper validation. Therefore, a strong effort from companies will be required to accomplish the new IVDR.
“it appeared that clinical utility and process standardization are the main key elements that can drive the introduction of a new test”
it appeared that clinical utility and process standardization are the main key elements that can drive the introduction of a new test in clinics. However, for the full introduction in clinical routine diagnostics, the cost of the test should be considered, and still is a key challenge to be addressed, except only for those assays targeting few mutations. However, the new IVDR, that for some aspects is still lacking clarity, will require an extensive validation of all the elements of the flow composing the assay, including for instance the software for analysis that in the new regulation is considered as a “Medical Device per se” if its utilization is providing clinical information to the patient status. This is a dramatic difference compared to the previous IVDD and it is expected to strongly impact, limit or delay the implementation and introduction in the clinic of many diagnostic assays including liquid biopsy tests. Moreover, LDT assays, which so far have been developed in the context of liquid biopsy, will be incorporated within the IVDR specifications of “in vitro medical device” used for diagnostics, impeding their utilization in the market without proper validation. Therefore, a strong effort from companies will be required to accomplish the new IVDR.
You’ve recently published a paper on the role of clustered circulating tumor cells in early breast cancer; Can you share with our readers some insights on this work?
Our work has highlighted for the first time the possibility to detect CTC clusters in early breast cancer opening the perspective to evaluate this blood biomarker in managing therapeutic decision, although further studies are required to correctly address the therapeutic relevance of these biomarkers in the clinics. We believe that this important finding has been obtained thanks to the standardized handling of the sample and our perfectly defined pre-analytical procedure for blood collection and sample preparation. Our proprietary SBS slide combined with our See.d, an automated platform for WBC seeding and plasma separation from fresh blood collected in EDTA installed at the point of blood collection, allow
the unbiased recovery of all the relevant cellular components, without enrichment, shortly after blood withdrawal, ensuring to maintain clinical informativity of the sample itself for CTC detection, preventing biomarkers degradation or alteration due to adding of preservatives on sample and long storage time before processing. The biological integrity of the sample and the precise standardization of the pre-analytical process are the two first elements that strongly influence the possibility to provide reliable clinical results from a diagnostic assay: processing fresh blood at the point of blood collection with our automated standardized instrument See.d, to obtain cellular sample for CTCs detection on slides and plasma to extract cfDNA or other biomarkers (exosomes, cfRNAs…) from the same collection tube, will ensure the best preparation of the sample, comparable results among different clinical sites and the possibility to perform a robust multi-analyte liquid biopsy test.
Innovation has always outpaced the regulatory frameworks; Can you share some key regulatory aspects that had a direct influence on the test designed by Tethis?
Most of the Liquid Biopsy tests so far have been developed as LDTs; regulatory authorities have therefore faced the multiplicity of these new assays and forced to introduce harmonization and standardization to have a clearer view of the risk assessment of these new diagnostics procedures:
Tethis test fulfills the specification for an LDT assay therefore it will require following the new IVDR instructions.
