Implementation science in hemato-oncology molecular diagnostics in France via the Groupe des Biologistes Moléculaire des Hémopathies Malignes (GBMHM)

Abstract

Implementation science in health has been defined as the study of methods to promote the adoption and integration of evidence-based practices, interventions, and policies into routine health care and public health settings.¹ Such approaches are essential to optimize societal benefit from published evidence-based innovation. In the case of hematological malignancies (HMs), the exponential increase in molecular genetic testing comes with challenges to offer them to all patients. Different attempts have been developed in European countries but in a heterogeneous fashion depending on a variety of factors.² In France, members of the French Hematology Society (Société Française d'Hématologie, SFH) created in 2005 the association of molecular biologists for HMs (Groupe des Biologistes Moléculaires des Hémopathies Malignes, GBMHM), a non-profit scientific network that organizes continuing medical education, concerted actions, and external quality assessment (EQA) for molecular diagnostics of hematological cancers. Most GBMHM activities represent implementation scientific approaches, designed to optimize molecular hematology at a national level. The present report summarizes these activities, as a contribution to adaptation of the 2017/746 In Vitro Diagnostic Medical Devices Regulation (IVDR).³

The GBMHM EQA system started in 2005 with the help of national health care authorities, which were eager to sustain innovative biology while respecting performance and safety issues. We initially piloted four tests for a national EQA program within the aforementioned RuBIH1 program (BCR::ABL1 transcript detection and quantification, JAK2^V617F detection, and IG/TR lymphoid clonality assessment). The successful pilot was then incremented with 12 other programs, as detailed.⁸ From 2014 onward, the program has been financed by billing participating health institutions. EQA is based on two principles: (1) sample exchange campaigns, and (2) feedback meetings for the promotion of standardization and ongoing medical education.⁹ To ensure full objectivity, the organization of sample exchange campaigns, including evaluation of results, is managed by a university hospital-based not-for-profit platform, employing non-GBMHM members, but with feedback meetings organized with GBMHM experts, often those involved in corresponding European standardization.

It should be noted that a certain degree of post-market device evaluation, such as the GeneXpert for BCR::ABL1 quantification, is also addressed through sample exchange campaigns. This approach is used for both CE-IVD (e.g., JAK2^V617F and lymphoid clonality) and in-house tests (the majority, and all rare targets). This approach has produced clear improvements, including superior analytical performance, technical standardization, and homogenization of interpretation, including for In-House IVDs (IH-IVD), also known as laboratory-developed tests.⁹

Accreditation of French medical biology laboratories is the responsibility of the French Accreditation Committee (COFRAC),¹⁰ which ensures that processes comply with the ISO15189 standard. Accreditation is compulsory for all CE-IVD molecular tests in onco-hematology and recommended for innovative tests, including IH-IVDs. The latter is more extensive than for CE-IVDs, consisting of a more detailed assessment of the method's performance. The difficulty of accrediting rare tests has been the subject of GBMHM recommendations. In these situations, if a laboratory has mastered the same technology for frequent analyses and for which it has been able to demonstrate accuracy during EQA, only limited verification of performance is proposed.¹¹ Increased understanding of the way accreditation is handled across Europe would aid identification of best practices among different countries/regions, which would in turn facilitate the implementation of the IVDR. The 79 molecular diagnostic laboratories affiliated with the GBMHM are located throughout France (Figure 1A). In 2024, 91% had started the accreditation process and 39% of laboratories had accredited all their tests (Figure 1B). The most frequently accredited tests are JAK2, BCR::ABL1, and lymphoid clonality, which have an established EQA, but it is noteworthy that 61% of laboratories performing high-throughput sequencing (HTS) are accredited or in the process thereof (Figure 1C). The majority of GBMHM laboratories use CE-IVD kits for frequent analyses and IH-IVD for infrequent analyses (fusion transcripts other than BCR::ABL1) or those that require regular improvements adapted to changes in knowledge, such as HTS (Figure 1D). The majority of molecular genetic tests are IVDR Class C (approximately 25% of the 40 000 tests estimated to be on the European CE-IVD market) but given the rarity of HM (8% of cancers overall, 40% of pediatric cancers) most molecular tests are IH-IVD. In a recent European survey, Hematology laboratories use IH-IVDs in approximately 30% of tests, and somatic/cancer genetic laboratories in over 50%.¹²

In 2021 and 2022, the French Ministry of Health identified 597 Medical Biology Reference Laboratories (Laboratoires de biologie médicale de reference, LBMR) for one or more biological tests or specific pathologies, to provide expertise on performing, interpreting, and advising on test use.¹³ The two calls led to the designation of 59 hematology LBMR (10% of national LBMR), selected by a national committee from the discipline. The committee chose to prioritize laboratories that could demonstrate their ability to integrate different techniques (cytology, immunophenotyping, cytogenetics, and molecular biology) to produce a precise, state-of-the-art diagnosis of a specific pathology or group of pathologies, rather than those performing a specific technique. As such, they resemble the Specialised Integrated Hematological Malignancy Diagnostic Service developed in the UK under the auspices of the NICE competent authority since 2003.¹⁴ For common HM, the evaluation committee chose to encourage a network of regional laboratories, to guarantee territorial coverage but for the rarest, a more centralized LBMR strategy was chosen to exploit national expertise. This network of LBMRs should become a progressive driving force in the development of hematology diagnostics, from medical and HTA evaluation to advising health authorities on strategies for optimizing the relevance of biological procedures, including within the confines of the evolving European HTA regulation (HTAR), which entered into force in January 2025.¹⁵ IVDR requirements include proof of clinical relevance and post-market surveillance. The LBMR reference networks could contribute to this process, provided that specific resources are earmarked for these laboratories to carry out the missions for which they were created. The precise mechanisms and conditions of such a partnership are still being identified, as are the practicalities of IVDR implementation for high-risk/personalized diagnostics, whether they be CE-IVD or IH-IVD.

Given the therapeutic impact and cost of molecular testing in cancer, the lack of rationalization and appropriate reimbursement is a major, unmet public health need.¹⁶ Identification of appropriate methodology is required to optimize patient safety and equal access and deliver robust, state-of-the-art diagnoses while protecting innovation. The French Ministry of Health piloted an incentive system to promote innovation in diagnostics in 2015 under the name RIHN (Réferentiel des actes Innovants Hors Nomenclature), which translates into a list of innovative and as-yet unlisted diagnostic tests. The objective was to allow a period during which innovative tests would be funded through an earmarked budget, while subjected to HTA via collection of data on their usefulness and economic impact, to be eventually listed (or not) on the social Health Insurance schedule and reimbursed. The current temporary “list-price” funding for targeted HTS panels is 882.90€ for <20 kb sequenced; 1503.90€ if >20 kb and <100 kb; and 2205.90€ if >100 kb and <500 kb, although in practice it is much lower since the total reimbursement budget is fixed. The GBMHM was able to leverage research funding through the aforementioned ministerial health economic research program, and conduct a targeted HTS cost consequence analysis in five categories of pediatric and adult HM.⁶ HTS results were considered to impact management for 73.4% of almost 4000 prescriptions (two-thirds myeloid, one-third lymphoid), including evaluation of prognostic risk in 34.9% and necessary for treatment adaptation (actionable) in 19.6%, but having no immediate individual therapeutic impact in 18.9%. When comparing costs to current reimbursement, the activity threshold that rendered unit costs relatively independent of annual activity was around 700 samples per year with current equipment and processes. Unit costs per target-gene/hotspot sequenced were comparable with capture (3.6–11.3€) versus amplicon (10.6–14.7€) approaches, with greater informativity/flexibility for the former. The GBMHM and SFH also provided guidelines on the principal indications for HTS analysis in onco-hematology, at the request of the national competent authority (HAS or Haute Authorité Sanitaire). An updated RIHN (2.0) framework was published in 2023,¹⁷ with greater emphasis on the need to collect evidence on clinical and economic test impacts, in keeping with IVDR requirements. This update was prompted by the fact that few diagnostic tests were actually subjected to proper assessment with clinical and economic data collection, due to the lack of methodological resources and know-how. The onco-hematology tests currently financed through the first wave of RIHN, and in particular the HTS panels, will be assessed by the HAS during the coming years.¹⁸

The European diagnostic community welcomed the general objectives of the IVDR, but difficulties with its implementation have made it evident that modifications, including based on the advice and experience of stakeholders such as diagnostic health care providers, are necessary. The GBMHM, based on the experience described earlier, aligns itself with the position of the Biomedical Alliance in Europe on the IVDR review¹⁹ and, more specifically, proposes the initiatives listed in Table 1 for consideration. They include the following: involvement of European EQA structures for IVD device performance and post-market surveillance monitoring; diversification of European Commission diagnostic expert panels, in particular to address specific concerns such as those for molecular genetics; incentives for drafting European guidelines on Just Prescription to promote relevant use of laboratory tests; set-up European Rare Diagnostic Networks of national (LBMR-like) reference laboratories; encourage concerted actions for standardization of In-House Diagnostics in Europe; take advantage of ISO15189 accreditation to strengthen the quality and safety of IVD devices across Europe; consider simplifying early registration procedures for innovative IVD devices, while respecting the benefit-risk balance; revise IVDR provisions applying to IH-IVD (article 5.5) to prevent monopolies on tests for rare targets; envisage appropriate provisional reimbursement schemes, with conditions that optimize evaluation of clinical relevance; and pave the way for the development of methodologies for HTA of diagnostics.

The GBMHM implementation scientific initiatives described here illustrate the force of collective national academic action in concertation with health economists, HTA experts, national ministries, agencies, and competent authorities. Our objective in describing these initiatives is that such national experimentation, often inspired by European concerted actions, might be useful for the European diagnostic community as we adapt to IVDR and HTAR, as well as evolving European regulations on clinical trials and data management. Similar initiatives in other European countries undoubtedly exist. Such implementation scientific approaches will hopefully provide useful information for regulators, policymakers, and payers responsible for developing optimal, equal access to state-of-the-art diagnostics in cancer throughout and beyond Europe.

Jean-Michel Cayuela, Pierre Sujobert, Pascale Flandrin-Gresta, Anne-Sophie Alary, Carole Maute, Meryl Darlington, Isabelle Durand-Zaleski, Olivier Kosmider, and Elizabeth Macintyre drafted the article. All authors discussed the proposals and contributed to the final manuscript.

J. M. C. received honoraria as a speaker from Novartis Pharma and Incyte Biosciences. P. F. G. received honoraria as a speaker from Novartis Pharma and Incyte Biosciences and funding for a congress from Servier. C. M. received honoraria as a speaker from Incyte Biosciences. I. D. Z. received honoraria/consulting fees from BMS, MSD, and Roche. E. M. received honoraria as a speaker from Servier. Other authors have no conflicts of interest to disclose.

The authors declare no sources of funding.