COIN | Organization

WP lead: Ed Schuuring (UMCG)

Several analytical factors, like the collection, reprocessing and storage of plasma, centrifugation protocols and cfDNA isolation methods, influence the analysis of ctDNA and have an impact on the results and their interpretation for the choice of treatment . Based on literature and experiences of COIN members we will develop best practice guidelines regarding the critical factors for pre-analytical handling of ctDNA, based on consensus. 

For the analytical phase different methods are in use in the Netherlands. Within the COIN initiative we will develop a COIN EQA scheme for inter-laboratory comparison of methods and results. Reference samples will be analyzed by the participating labs, after which we will evaluate the different used methods with respect to the detection of specific clinically relevant mutations and the sensitivity rate.  Evaluation of the results of the EQA scheme will provide insight in the correct procedures for ctDNA analyses for individual laboratories. These data, combined with information on the total costs of analysis, will serve as input for the cost-effectiveness analysis and for designing optimal diagnostic strategies by WP 2. The results will also be used in WP 5 to develop Standard Operation Procedures (SOP’s) and in WP 3 to develop standardized, structured, reporting formats for ctDNA in clinical practice.

WP lead: Veerle Coupé (AUMC)

Early HTA of a new technology based on observational studies is challenging, because generally information about the course of disease under alternative treatment decisions is lacking. 

However, using observational data, a mathematical model of the course of the disease under current treatment (disease-free survival, progression-free survival, overall survival) in relation to ctDNA results and other patient and tumor features may be developed. In addition, observational data can establish the appropriate modeling methodology for early assessment of the cost-effectiveness of ctDNA for various clinical needs. Concerning expected outcomes under alternative treatment decisions, at this time only a series of scenario analyses can be performed. Using the already ongoing observational studies included in COIN, a conceptual modeling framework for early HTA of ctDNA will be established. This framework will be used to make an early cost-effectiveness assessment of the different clinical applications of ctDNA: target profiling, early response assessment and treatment evaluation.

WP leads: Marjolijn Ligtenberg (RadboudUMC) & Gerrit Meijer (NKI/AVL)

Standardized processing and reporting pipelines are conditional to sustain expertise and data obtained in research setting but also for data generated in the context of clinical care. 

This will require data to be FAIR (Findable, Accessible, Interoperable and Reusable). To this end COIN will use data/IT/biobank/ELSI services provided by HEALTH-RI/BBMRI-NL/TraIT, building on expertise of ctDNA studies that already make use of services such as Catalogue, tranSMART and cBioPortal. The COIN consortium will set a standard coding system for ctDNA data to allow interoperability of data. Standardized structured diagnostic reporting will be developed in collaboration with PALGA, one of the partners in the COIN consortium, and the respective medical disciplines involved.

WP lead: Thijs van Vegchel (IKNL)

The aim of WP 4 is to develop a tool to support clinical decision making, which will support the implementation of COIN-guidelines in daily clinical practice.  To combine traditional evidence based recommendations for diagnostics and treatment with expert knowledge as well as with complementary knowledge generated from (trial) data, we will combine a rule based and and a data driven approach. prediction model approaches. 

In cooperation with experts in the fields of CRC and NSCLC we will develop decisional algorithms to determine when ctDNA analyses is indicated and what line of treatment is recommended. For this we will use (inter-)national coding systems (SNOMED-CT), (FAIR) principles for the re-use of data and healthcare information standards (HL7 FHIR) for the exchange of data. This will result in interoperability, enabling decisional algorithms to be integrated in the various existing Electronic Health Records systems, like EPD’s and labsystems.

WP lead: Ron van Schaik (ErasmusMC)

Clinical implementation of ctDNA analysis requires procedures to comply with the ISO15189 standard.

Within the COIN consortium we bring together both research and clinical laboratories, allowing us to establish clinical grade SOPs for ctDNA workflows based on the results from the described steps.

Guidelines and standard operating procedures initially focusing on lung cancer and CRC will be composed in such way that results can be applied to other tumor types. COIN will closely align with the PATH-project.

WP lead: Kim Monkhorst (NKI/AVL)

For implementation, not only clinical utility and cost-effectiveness count, but also a clear reimbursement strategy of ctDNA diagnostics is needed. 

In addition to a good structure for reimbursement, entitlement (when is which diagnostics reimbursed or not?) also plays an important role. 

In addition to the recently renewed reimbursement structure, the aim is to set up a consultative body in which the effectiveness and positioning of (new) diagnostics can be discussed. To this end we will engage with relevant stakeholders like ZIN and NZA, health insurers, as well as medical associations like NVVP, VKGN, NVMO NVALT and NVKC. This consultative body will be called ‘commissie BeOordeling Diagnostiek’ (cieBOD).

WP lead: Remond Fijneman (NKI/AVL)

MEDOCC-CrEATE will be the first Dutch ctDNA biomarker-driven intervention trial. This study aims to establish the clinical value of ctDNA diagnostics for preventing undertreatment in stage II Colon Cancer. It is being investigated whether adjuvent treatment after surgery in ctDNA-positive patients leads to improved, disease-free survival.

View the MEDOCC-CrEATE study protocol.  

Health Technology Assessment (HTA) is an integral part of this study to compare the impact of ctDNA diagnostics on costs and health benefits with that of the Standard of Care (SoC).

MEDOCC-CrEATE is performed as a sub-study of the Prospective Dutch

CRC Cohort (PLCRC). Principal investigators of this multidisciplinary study include Miriam Koopman and Geraldine Vink (UMCU), Veerle Coupé (AUMC), Daan van den Broek and Gerrit Meijer (NKI/AVL).