Letter addressed to: MDCG IVD Group, DG Sante - Unit B6, EMA
Representing cancer patients, diagnostic and laboratory industry experts and the pharmaceutical industry, we write to you with serious concerns related to the unaddressed implementation challenges faced by the healthcare sector across Europe ahead of the date of application of the In Vitro Diagnostic Regulation (IVDR). While we agree that well-regulated diagnostics are critical for patient access to high quality testing, various stakeholders within healthcare are concerned that the infrastructure supporting the transition toward a new regulatory system for diagnostics under the IVDR is not ready. Furthermore, it will not be ready on time to ensure the continued availability of tests required for patients whose conditions rely on the delivery of appropriate in vitro diagnostics.
With this letter, we would like to highlight gathered data that will provide insights into the issues faced by cancer patients where testing is vital to continued access to life-saving innovative precision medicines. While companion diagnostics represent one aspect of IVD utility within Europe it is, in fact, a very critical use as it determines patient access to potentially life-saving medicines.
With a year to go before the date of application of the IVDR (26 May 2022), the infrastructure necessary for its implementation is lacking. This includes EUDAMED, Reference Laboratories and Notified Body (NB) capacity . A major concern is that while there were 22 NBs under the IVD Directive (IVDD), there are currently only 4 NBs designated under the IVDR. Further, under the new regulation 80% – 90% of IVDs will require conformity assessment by a NB, which is a 600-700% increase in the NB workload, while previously under the IVDD only 10 – 20% of products required certification. Additionally, current device certification capacity is so limited that product files are taking on average 9 – 12 months to review regardless of the device classification. Clinical practice across the EU relies heavily on the use of tests developed by laboratories in-house or within a single hospital or institution. To continue using these tests, laboratories will need to meet the exemptions listed in the new requirements highlighted in the IVDR. This will impact patient testing.
These challenges are compounded by the restriction of on-site audits due to the COVID-19 pandemic. Moreover, 70% of small and medium IVD manufacturers don’t have a NB under the IVDR .
Even if the infrastructure required to support the transition toward the IVDR were put in place and fully functioning within this year, NBs could not possibly take on and manage this immense workload in such a short period of time to avoid market disruption.
A severe consequence of this will be that from 26 May 2022, most diagnostics currently on the EU market will not be authorised for use in the healthcare systems of EU Member States, causing a detrimental impact on the management of cancer patients across the EU. In a case study prepared by Diaceutics , 110,575 metastatic non-small cell lung cancer (NSCLC) and ovarian cancer patients will require testing for actionable biomarkers to have access to approved innovative and life-saving precision medicines in Europe in the year following IVDR implementation.
We estimate that the reduction in biomarker testing due to the implementation of the IVDR will impact the lives of as many as 65,000 NSCLC and ovarian cancer patients per year who will miss out on identifying the right treatment for the right patient.
This number will be greater if we consider all cancer types which require a biomarker test for access to a precision medicine.
It is sobering to note that the above case study considers only oncology biomarker tests which make up a small fraction of the diagnostic tests currently in use in Europe.
As diagnostic results are required for ~70% of clinical decisions , this is likely to adversely impact clinical management of millions of EU patients. It will also hinder Europe’s Beating Cancer Plan which is striving to build on the promise of personalised medicine for cancer prevention, diagnosis and treatment through new technologies, research and innovation.
Given the potential dire impact of this situation with only a year before the IVDR comes into full force, we appeal to you to consider these urgent measures:
• an initial one-year postponement of the IVDR date of application with immediate effect;
• following this postponement, a phased IVDR rollout which prioritises NBs’ assessment of high-risk impact diagnostic tests (i.e. starting with class D devices);
• accelerated designation of sufficient NBs, prompt release of key guidance documents and full functionality enabled in Eudamed to ensure that the critical regulatory infrastructure required is in place on the new Date of Application.
As Vice President Schinas of the European Commission said:
Cancer care is no longer the responsibility of the health sector alone. The success of Europe's Beating Cancer Plan requires engagement and buy-in from a wide range of sectors and stakeholders, a whole-of-society effort
We would therefore urge you to take action now to safeguard the continued and comprehensive access of patients and the healthcare system to life-saving and innovative diagnostic tests across the EU, and to ensure that the implementation of the IVDR does not have a detrimental impact on the care and lives of thousands of cancer patients.
Yours sincerely, Ken Mastris, ECPC President Nathalie Moll, EFPIA Director General Peter Keeling, CEO Diaceutics
Appendix Diaceutics Case Study Methodology
In order to produce a real-world analysis of this critical issue, Diaceutics has analysed insights from the world’s richest source of diagnostic testing data enabled by its DXRX platform to model the potential patient impact.(1,2) The following is a summary of the methodology used.
Lung cancer incidence rates were sourced from the International Agency for Research on Cancer (IARC) database for the EU-27 Member States. To these patient numbers the NSCLC fraction was applied and then the metastatic NSCLC rate. To the metastatic NSCLC patient cohort in each Member State proportions of the following actionable mutation were utilized; KRAS, EGFR, ALK, BRAF, ROS1, and NTRK. [3–8] PD-L1 expression rates (cut-off at > 50%) were determined from the remaining cohort with no druggable mutation. Employing EGFR tests as a proxy for next-generation sequencing (NGS), laboratory developed tests (LDTs) to commercial kit ratios were determined from Diaceutics DXRX database, and PD-L1 LDT to commercial kit ratios were also calculated.
Ovarian cancer incidence rates were also sourced from IARC for the EU-27, the metastatic rate applied, and BRCA mutation proportion employed.[1,10,11] BRCA LDT to commercial kit ratios were ascertained from the DXRX database.
A scenario of complete non-availability of LDT and 50% non-availability of commercial kits was assumed under the application of the IVDR and these proportions implemented to calculate the number of patients who will potentially be lost to precision therapy.
1. Diaceutics. DXRX - The Diagnostic Network. [Internet]. 2021 [cited 2021 May 17]. Available from: https://www.dxrx.io/en/
2. Smart D, Lawler M, Kearney S, Tops B, Wessels E, Henderson R, et al. Impact analysis of the IVDR on diagnostic practices & patient care across the EU: Lessons from the COVID-19 pandemic [Internet]. 2021. Available from: https://lp.diaceutics.com/ivdr-working-group-paper/
3. Ferlay, J, Ervik, M, Lam, F, Colombet, M, Mery, L, Piñeros, M, Znaor, A, Soerjomataram, I, Bray F. Global Cancer Observatory: Cancer Today [Internet]. International Agency for Research on Cancer. 2020. Available from: https://gco.iarc.fr/today
4. Campbell D, O’Day K, Hertel N, Penrod JR, Manley Daumont M, Lees M. The present and future burden of previously treated advanced non-small cell lung cancer (NSCLC) by histology and line of therapy in France, Germany, Italy, and Spain: model-based predictions. Popul Health Metr. 2018;16(1):1–8.
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8. Alvarez JGB, Otterson GA. Agents to treat BRAF- mutant lung cancer Molecular pathways Evidence for BRAF and MEK inhibitors combination for NSCLC. Drugs Context. 2019;8:31–5.
9. Bergethon K, Shaw AT, Ou SI, Katayama R, Lovly CM, Mcdonald NT, et al. ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers. J Clin Oncol. 2021;30(8):863–70.
10. Farago AF, Taylor MS, Zhu VW, Boyle TA, Arcila ME, Horick NK, et al. Clinicopathologic Features of Non – Small-Cell Lung Cancer Harboring an NTRK Gene Fusion. JCO Clin Cancer Informatics. 2018;2:1–12.
11. Dietel M, Savelov N, Salanova R, Micke P, Bigras G, Hida T, et al. Real-world prevalence of programmed death ligand 1 expression in locally advanced or metastatic non–small-cell lung cancer: The global, multicenter EXPRESS study. Lung Cancer [Internet]. 2019 Aug 1;134:174–9. Available from: https://doi.org/10.1016/j.lungcan.2019.06.012
12. Lengyel E. Ovarian Cancer Development and Metastasis. Am J Pathol [Internet]. 2010;177(3):1053–64. Available from: http://dx.doi.org/10.2353/ajpath.2010.100105
13. Hall MJ, Reid JE, Burbidge LA, Pruss D, Deffenbaugh AM, Frye C, et al. BRCA1 and BRCA2 Mutations in Women of Different Ethnicities Undergoing Testing for Hereditary Breast-Ovarian Cancer. Cancer. 2009;115(10):2222–33.