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Letter from EFPIA ECPC and Diaceutics calls for postponed application and phased implementation of the in vitro diagnostic Regulation

28 May, 2021

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.[1] To these patient numbers the  NSCLC fraction was applied and then the metastatic NSCLC rate.[2] 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.[9] 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.

References 

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.  
5. Adderley H, Blackhall FH, Lindsay CR. EBioMedicine KRAS-mutant non-small cell  lung cancer : Converging small molecules and immune checkpoint inhibition.  EBioMedicine [Internet]. 2019;41:711–
6. Available from:  https://doi.org/10.1016/j.ebiom.2019.02.049 6. Zhang Y, Yuan J, Wang K, Fu X. The prevalence of EGFR mutation in patients with  non-small cell lung cancer : a systematic review and meta-analysis. Oncotarget.  2016;7(48):9–13.  
7. Desai A, Mohammed T, Rakshit S, Krull J. 21P The Landscape of ALK Alterations in  Non-Small Cell Lung Cancer. In: Journal of Thoracic Oncology [Internet]. International  Association for the Study of Lung Cancer. Published by Elsevier Inc.; 2021. p. S707.  Available from: http://dx.doi.org/10.1016/S1556-0864(21)01863-3
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.


About Diaceutics

At Diaceutics we believe that every patient should get the precision medicine they deserve. We are a data analytics and end-to-end services provider enabled by DXRX - the world’s first Network solution for the development and commercialization of precision medicine diagnostics. 

Diaceutics has worked on every precision medicine brought to market and provides services to 36 of the world’s leading pharmaceutical companies. We have built the world’s largest repository of diagnostic testing data with a growing network of 2500 labs in 51 countries.