Abstract
The background to this debate is now well-known: an EU policy decision to tighten controls on the devices and diagnostics sector led to the adoption of a regulation in 2017 with a schedule for implementation over coming years – a timetable extended still further by last-minute legislation in early 2022, to provide the sector and regulators with more time to adapt to the changes. Discussions among experts organised in April by the European Alliance for Personalized Medicine (EAPM) exposed continuing challenges that cannot be fully resolved by the recent deferral of implementation deadlines. One salient problem is that there is little awareness of the In Vitro Diagnostic Regulation (IVDR) across Europe, and only limited awareness of the different structures of national systems involved in implementing IVDR, with consequent risks for patient and consumer access to in vitro diagnostics (IVDs). The tentative conclusion from these consultations is that despite a will across the sector to seek workable solutions, the obstacles remain formidable, and the potential solutions so far proposed remain more a matter of aspirations than of clear pathways.
Funding source: PROMISE- Personalized Medicine Inquiry-Based Education Co-funded by the Erasmus + Programme of the European Union
Award Identifier / Grant number: 2019-1-HR01-KA203-061010
Acknowledgments
Denis Horgan developed the concept, orientation, and overall narrative for this manuscript. We would like to thank the members of the European Alliance for Personalised Medicine (EAPM), and the representatives of the European Commission and Member States for their kind input. All co-authors of this manuscript together with Petra Zoellner, Maurizio Sanguinetti, Rositza Krasteva, Charis Girvalaki and Bart R. Lubbers participated on roundtables organized by EAPM. We thank them all for their valuable and kind inputs. Klark Mullen, Associate Director, Thera-peutic Area Government Affairs, Astellas Pharma Europe Ltd, provided expert input to the draft. The organized panel was facilitated by sponsorship of: Novartis, AstraZeneca and Astellas Pharma.
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Research funding: This research received grant from PROMISE- Personalized Medicine Inquiry-Based Education Co-funded by the Erasmus + Programme of the European Union; Grant Agreement No.: 2019-1-HR01-KA203-061010.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Elizabeth Macintyre is a President of the European Hematology Association. D.H. and M.K. are employees of the European Alliance for Personalised Medicine, which receives funding from both the public and private sectors. France Dube is an employee of Astra Zeneca. Stan Jackson is an employee of Astellas Pharma.
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Informed consent: Not applicable.
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Ethical approval: Not applicable.
References
1. European Parlament, Council of the European Union. Regulation (EU) 2017/745 of the European parliament and of the council of 5 April 2017 on medical devices. Off J Eur Union 2017;60:1–175.Search in Google Scholar
2. Eureporter. EAPM: virtual conference around the corner, in-vitro diagnostic – Rocky road ahead! [Online]. Available from: https://www.eureporter.co/health/personalised-medicine/european-alliance-for-personalised-medicine-personalised-medicine/2021/10/20/eapm-virtual-conference-around-the-corner-in-vitro-diagsnostic-rocky-road-ahead/ [Accessed 25 May 2022].Search in Google Scholar
3. Alpert, S, Anastasi, V, Aronson, N, Durtschi, A, Faison, T, Fink, R, et al.. Developing clinical evidence for regulatory and coverage assessments in in vitro diagnostics (IVDs); 2019. Available from: https://mdic.org/wp-content/uploads/2019/08/Clinical-Evidence-IVD-Framework-FINAL.pdf.Search in Google Scholar
4. EUR-Lex. Consolidated text: regulation (EU) 2017/746 of the European parliament and of the council of 5 April 2017 on in vitro diagnostic medical devices and repealing directive 98/79/EC and commission decision 2010/227/EU [Online]. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02017R0746-20220128 [Accessed 25 May 2022].Search in Google Scholar
5. Nayak, S, Venkatesh, MP, TM PK. EU IVDR regulatory changes: an overview of requirements in (EU) 2017/746. Appl Clin Res Clin Trials Regul Aff 2020;7:237–43. https://doi.org/10.2174/2213476x07666200327143023.Search in Google Scholar
6. Payne, S, Hall, A. What is the IVDR. PHG Found; 2018. Available from: https://www.phgfoundation.org/briefing/what-is-the-ivdr.Search in Google Scholar
7. Spitzenberger, F, Patel, J, Gebuhr, I, Kruttwig, K, Safi, A, Meisel, C. Laboratory-developed tests: design of a regulatory strategy in compliance with the international state-of-the-art and the regulation (EU) 2017/746 (EU IVDR [in vitro diagnostic medical device regulation]). Ther Innov Regul Sci 2022;56:47–64. https://doi.org/10.1007/s43441-021-00323-7.Search in Google Scholar PubMed PubMed Central
8. Vogeser, M, Brüggemann, M, Lennerz, J, Stenzinger, A, Gassner, UM. Laboratory-developed tests in the new European union 2017/746 regulation: opportunities and risks. Clin Chem 2021;68:40–2. https://doi.org/10.1093/clinchem/hvab215.Search in Google Scholar PubMed
9. Stenzinger, A, Weichert, W. Impact of the novel in vitro diagnostic regulation (IVDR) of the European union on pathology laboratories. What’s important? Pathologe 2020;41(2 Suppl):129–33. https://doi.org/10.1007/s00292-020-00867-9.Search in Google Scholar PubMed
10. Hoffmüller, P, Brüggemann, M, Eggermann, T, Ghoreschi, K, Haase, D, Hofmann, J, et al.. Advisory opinion of the awmf ad hoc commission in-vitro diagnostic medical devices regarding in-vitro diagnostic medical devices manufactured and used only within health institutions established in the union according to regulation (Eu) 2017/746 (ivdr). GMS Ger Med Sci 2021;19:Doc08.Search in Google Scholar
11. Dagher, G, Becker, KF, Bonin, S, Foy, C, Gelmini, S, Kubista, M, et al.. Pre-analytical processes in medical diagnostics: new regulatory requirements and standards. N Biotech 2019;52:121–5. https://doi.org/10.1016/j.nbt.2019.05.002.Search in Google Scholar PubMed
12. Cobbaert, C, Capoluongo, ED, Vanstapel, FJLA, Bossuyt, PMM, Bhattoa, HP, Nissen, PH, et al.. Implementation of the new EU IVD regulation-urgent initiatives are needed to avert impending crisis. Clin Chem Lab Med 2022;60:33–43. https://doi.org/10.1515/cclm-2021-0975.Search in Google Scholar PubMed
13. European Commission. Proposal for a regulation of the european parliament and of the council amending regulation (EU) 2017/746 as regards transitional provisions for certain in vitro diagnostic medical devices and deferred application of requirements for in-house devices [Online]. Available from: https://ec.europa.eu/health/system/files/2021-10/md_2017-746-regulation_2021-amendment_en_0.pdf [Accessed 25 May 2022].Search in Google Scholar
14. Lubbers, BR, Schilhabel, A, Cobbaert, CM, Gonzalez, D, Dombrink, I, Brüggemann, M, et al.. The new EU regulation on in vitro diagnostic medical devices: implications and preparatory actions for diagnostic laboratories. HemaSphere 2021;5:e568. https://doi.org/10.1097/hs9.0000000000000568.Search in Google Scholar PubMed PubMed Central
15. van Drongelen, A, de Bruijn, A, Pennings, J, van der Maaden, T. The impact of the new European IVD-classification rules on the notified body involvement. Natl Inst Public Heal Environ 2018:1–32.Search in Google Scholar
16. Genzen, JR. Regulation of laboratory-developed tests: a clinical laboratory perspective. Am J Clin Pathol 2019;152:122–31. https://doi.org/10.1093/ajcp/aqz096.Search in Google Scholar PubMed PubMed Central
17. MDR. Placing on the market and putting into service [Online]. Available from: https://www.medical-device-regulation.eu/mdr-article-5-placing-on-the-market-and-putting-into-service/ [Accessed 25 May 2022].Search in Google Scholar
18. Kaul, KL, Sabatini, LM, Tsongalis, GJ, Caliendo, AM, Olsen, RJ, Ashwood, ER, et al.. The case for laboratory developed procedures. Acad Pathol 2017;4:1–21. https://doi.org/10.1177/2374289517708309.Search in Google Scholar PubMed PubMed Central
19. Vogeser, M, Brüggemann, M. Complex analytical procedures in diagnostic laboratories and the IVDR. Clin Chem Lab Med 2021;59:457–8. https://doi.org/10.1515/cclm-2020-1775.Search in Google Scholar PubMed
20. Vermeersch, P, Van Aelst, T, Dequeker, EMC. The new IVD Regulation 2017/746: a case study at a large university hospital laboratory in Belgium demonstrates the need for clarification on the degrees of freedom laboratories have to use lab-developed tests to improve patient care. Clin Chem Lab Med 2020;59:101–6. https://doi.org/10.1515/cclm-2020-0804.Search in Google Scholar PubMed
21. Burd, EM. Validation of laboratory-developed molecular assays for infectious diseases. Clin Microbiol Rev 2010;23:550–76. https://doi.org/10.1128/cmr.00074-09.Search in Google Scholar
22. Robinson, SA, Carter, AR, Brindley, DA. The changing regulatory landscape for laboratory developed tests. Regulatory Affairs Professionals Society (RAPS); 2021. Available from: https://www.raps.org/news-and-articles/news-articles/2021/8/the-changing-regulatory-landscape-for-laboratory-d.Search in Google Scholar
23. Bank, PCD, Jacobs, LHJ, Van Den Berg, SAA, Van Deutekom, HWM, Hamann, D, Molenkamp, R, et al.. The end of the laboratory developed test as we know it? Recommendations from a national multidisciplinary taskforce of laboratory specialists on the interpretation of the IVDR and its complications. Clin Chem Lab Med 2021;59:491–7. https://doi.org/10.1515/cclm-2020-1384.Search in Google Scholar PubMed
24. MDCG. Guidance on significant changes regarding the transitional provision under article 110(3) of the IVDR. Public Health [Online]. Available from: https://ec.europa.eu/health/latest-updates/mdcg-2022-6-guidance-significant-changes-regarding-transitional-provision-under-article-1103-ivdr-2022-05-04_en [Accessed 25 May 2022].Search in Google Scholar
25. MDCG. Clarification on “first certification for that type of device” and corresponding procedures to be followed by notified bodies [Online]; 2022. Available from: https://health.ec.europa.eu/latest-updates/mdcg-2021-22-rev1-clarification-first-certification-type-device-and-corresponding-procedures-be-2022-09-14_en [Accessed 25 May 2022].Search in Google Scholar
26. European Commission. Guidance – MDCG endorsed documents and other guidance [Online]. Available from: https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed-documents-and-other-guidance_en [Accessed 25 May 2022].Search in Google Scholar
27. MDCG. Transition to the MDR and IVDR – notified body capacity and availability of medical devices and IVDs [Online]. Available from: https://health.ec.europa.eu/latest-updates/mdcg-2022-14-transition-mdr-and-ivdr-notified-body-capacity-and-availability-medical-devices-and-2022-08-26_en [Accessed 25 May 2022].Search in Google Scholar
28. MDCG. Designation, re-assessment and notification of conformity assessment bodies and notified bodies [Online]. Available from: https://health.ec.europa.eu/latest-updates/mdcg-2022-13-designation-re-assessment-and-notification-conformity-assessment-bodies-and-notified-2022-08-10_en [Accessed 25 May 2022].Search in Google Scholar
29. European Commission. Setting the scene for EU reference labs for high-risk diagnostics [Online]. Available from: https://health.ec.europa.eu/latest-updates/setting-scene-eu-reference-labs-high-risk-diagnostics-2022-06-21_en [Accessed 25 May 2022].Search in Google Scholar
30. EMERGO. European notified bodies issue updates on MDR, IVDR implementation challenges [Online]. Available from: https://www.emergobyul.com/blog/2022/01/european-notified-bodies-issue-updates-mdr-ivdr-implementation-challenges [Accessed 25 May 2022].Search in Google Scholar
31. Udugama, B, Kadhiresan, P, Kozlowski, HN, Malekjahani, A, Osborne, M, Li, VYC, et al.. Diagnosing COVID-19: the disease and tools for detection. ACS Nano 2020;14:3822–35. https://doi.org/10.1021/acsnano.0c02624.Search in Google Scholar PubMed PubMed Central
32. Valla, V, Alzabin, S, Koukoura, A, Lewis, A, Nielsen, AA, Vassiliadis, E. Companion diagnostics: state of the art and new regulations. Biomark Insights 2021;16:1–14. https://doi.org/10.1177/11772719211047763.Search in Google Scholar PubMed PubMed Central
33. European Commission. Questions and answers: stronger rules for placing medical tests on the market [Online]. Available from: https://ec.europa.eu/commission/presscorner/detail/en/QANDA_22_3289 [Accessed 25 May 2022].Search in Google Scholar
34. EFPIA. Unlocking the potential of precision medicine in Europe – improving cancer care through broader access to quality biomarker testing [Online]. Available from: https://efpia.eu/news-events/the-efpia-view/statements-press-releases/unlocking-the-potential-of-precision-medicine-in-europe-improving-cancer-care-through-broader-access-to-quality-biomarker-testing/ [Accessed 25 May 2022].Search in Google Scholar
35. Kleinert, S, Horton, R. Pathology and laboratory medicine: the Cinderella of health systems. Lancet 2018;391:1872–3. https://doi.org/10.1016/s0140-6736(18)30457-4.Search in Google Scholar
36. Rushforth, A, Greenhalgh, T. Personalized medicine, disruptive innovation, and “trailblazer” guidelines: case study and theorization of an unsuccessful change effort. Milbank Q 2020;98:581–617. https://doi.org/10.1111/1468-0009.12455.Search in Google Scholar PubMed PubMed Central
37. European Observatory on Health Care Systems. Health care systems in transition [Online]. Available from: https://www.euro.who.int/__data/assets/pdf_file/0010/80776/E68952.pdf [Accessed 25 May 2022].Search in Google Scholar
38. Adashi, EY, Cohen, IG. SARS-CoV-2 laboratory-developed tests: integrity restored. JAMA – J Am Med Assoc 2022;327:1229–30. https://doi.org/10.1001/jama.2022.3382.Search in Google Scholar PubMed
39. Busse, R, Klazinga, N, Panteli, D, Quentin, W, editors. Improving healthcare quality in Europe: characteristics, effectiveness and implementation of different strategies. Copenhagen, Denmark: European Observatory on Health Systems and Policies; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549276/.Search in Google Scholar
40. MDCG. Guidance on borderline between medical devices and medicinal products under regulation (EU) 2017/745 on medical devices [Online]. Available from: https://ec.europa.eu/health/system/files/2022-04/mdcg_2022-5_en_0.pdf [Accessed 25 May 2022].Search in Google Scholar
41. MDCG. Q & A on the interface between regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) [Online]. Available from: https://ec.europa.eu/health/system/files/2022-05/mdcg_2022-10_en.pdf [Accessed 26 May 2022].Search in Google Scholar
42. EMA. Evolving framework co-development medicinal products companion diagnostics [Online]. Available from: https://www.ema.europa.eu/en/documents/presentation/presentation-evolving-framework-co-development-medicinal-products-companion-diagnostics-falk-ehmann_en.pdf [Accessed 25 May 2022].Search in Google Scholar
43. EMA. General: regulatory and procedural guidance. Available from: https://www.ema.europa.eu/en/general-regulatory-procedural-guidance [Accessed 25 May 2022].Search in Google Scholar
44. MDCG. Guidance on significant changes regarding the transitional provision under article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD [Online]. Available from: https://ec.europa.eu/health/system/files/2020-09/md_mdcg_guidance_significant_changes_annexes_en_0.pdf [Accessed 25 May 2022].Search in Google Scholar
45. Horgan, D, Ciliberto, G, Conte, P, Curigliano, G, Seijo, L, Montuenga, LM, et al.. Bringing onco-innovation to Europe’s healthcare systems: the potential of biomarker testing, real world evidence, tumour agnostic therapies to empower personalised medicine. Cancers 2021;13:583. https://doi.org/10.3390/cancers13030583.Search in Google Scholar PubMed PubMed Central
46. Eureporter. EAPM: successful IVDR meeting points the way to future collaborations [Online]. Available from: https://www.eureporter.co/health/personalised-medicine/european-alliance-for-personalised-medicine-personalised-medicine/2021/07/23/eapm-successful-ivdr-meeting-points-the-way-to-future-collaborations/ [Accessed 26 May 2022].Search in Google Scholar
47. MDCG. Harmonised administrative practices and alternative technical solutions until eudamed is fully functional. IVDR [Online]. Available from: https://health.ec.europa.eu/latest-updates/mdcg-2022-12-harmonised-administrative-practices-and-alternative-technical-solutions-until-eudamed-2022-07-13_en [Accessed 25 May 2022].Search in Google Scholar
48. Lowe, S, Hill, D. Medical devices and the limits of UK regulatory autonomy. Insight – Centre for European Reform; 2021. Available from: https://www.cer.eu/sites/default/files/insight_med_devices_SL_DH_5.8.21.pdf.Search in Google Scholar
49. D’Avó Luís, AB, Seo, MK. Has the development of cancer biomarkers to guide treatment improved health outcomes? Eur J Health Econ 2021;22:789–810. https://doi.org/10.1007/s10198-021-01290-4.Search in Google Scholar PubMed PubMed Central
50. Horgan, D, Ciliberto, G, Conte, P, Baldwin, D, Seijo, L, Montuenga, LM, et al.. Bringing greater accuracy to europe’s healthcare systems: the unexploited potential of biomarker testing in oncology. Biomed Hub 2020;5:182–223. https://doi.org/10.1159/000511209.Search in Google Scholar PubMed PubMed Central
51. Horgan, D. EU health policy is on the brink of a spectacular own-goal that will harm patients and hamper innovation. Clin Chem Lab Med 2022;60:1–3. https://doi.org/10.1515/cclm-2021-1100.Search in Google Scholar PubMed
52. Geisler, C, Gaisa, NT, Pfister, D, Fuessel, S, Kristiansen, G, Braunschweig, T, et al.. Identification and validation of potential new biomarkers for prostate cancer diagnosis and prognosis using 2D-DIGE and MS. BioMed Res Int 2015;2015:454256. https://doi.org/10.1155/2015/454256.Search in Google Scholar PubMed PubMed Central
53. Jakobsen, NA, Hamdy, FC, Bryant, RJ. Novel biomarkers for the detection of prostate cancer. J Clin Urol 2016;9(2 Suppl):3–10. https://doi.org/10.1177/2051415816656121.Search in Google Scholar PubMed PubMed Central
54. Matuszczak, M, Schalken, JA, Salagierski, M. Prostate cancer liquid biopsy biomarkers’ clinical utility in diagnosis and prognosis. Cancers 2021;13:3373. https://doi.org/10.3390/cancers13133373.Search in Google Scholar PubMed PubMed Central
55. Provenzano, M, Allayeh, AK. Liquid biopsy to detect DNA/RNA based markers of small DNA oncogenic viruses for prostate cancer diagnosis, prognosis, and prediction. Front Oncol 2020;10:778. https://doi.org/10.3389/fonc.2020.00778.Search in Google Scholar PubMed PubMed Central
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