ESHG strongly recommends that Article 5-§5 conditions (d) to (i) for in-house exemptions are removed from the IVD Regulation, while conditions (a) to (c) are kept. Failure to do so will increase health care costs and jeopardize our ability to design precise “personalized” laboratory tests (necessary for precision medicine) and to adapt to shifting test needs (like repurposing instruments for covid-19 testing).
Regulation EU 2017/746 on in vitro diagnostic medical devices (the IVD Regulation) will be European law from May 26th, 2022. The intentions of the legislators have been appropriate: to secure quality of all kinds of medical diagnostic tests, and to make sure such tests are performed within the frame of the health care system. An apparently convenient means to obtain this is to demand industry standard CE marking of tests and instruments.
In-house exemption to CE marking
Since CE marking is too cumbersome and expensive for the low-volume specialized tests designed in many diagnostic laboratories, also as part of precision medicine, an in-house exemption to the requirement for CE marking has been made (article 5-§5). Such in-house tests are very common in medical genetics. However, this in-house exemption can only be invoked if several conditions are fulfilled (numbered a-i). One condition is that the laboratory must be accredited according to EN ISO 15189 or a similar nationally approved system. This condition makes much sense since such accreditation automatically implies quality management and risk evaluation (other requirements). More problematic, however, is condition (d): “the health institution justifies in its documentation that the target patient group’s specific needs cannot be met […] by an equivalent device available on the market”. In other words: If a CE marked commercial test exists that gives similar test results, that test must be used – and cost is not an issue.
Precision medicine out of control
So far commercial CE marked tests for rare conditions are exceptional, likely because the “market” is too small, i.e. not worth the investment. This may change when next generation (whole-exome or whole-genome) sequencing (NGS) is established as the basis for all kind of rare disease diagnostics; companies that now label their sequencing instruments “for research use only” may suddenly introduce a CE marked diagnostic “NGS-package” using the same instruments that will return a standardized set of sequencing data for local interpretation, like they have done for NIPT (non-invasive prenatal testing). This will turn in-house laboratory skills into an unaffordable luxury.
Furthermore, it will be too expensive to develop test reagents (like unique FISH probes) since the documentation requirements for non-commercial reagents in the IVD-Regulation goes beyond ISO 15189. The need for control measures that goes beyond EN ISO 15189 has not been documented as necessary for securing good laboratory quality. Practice in line with the well-established ISO-standard is in our view a sufficient quality control. We are, however, unsure if it is wise to allow national exemptions to this standard, like Article 5-§5 now allows. If Article 5-§5 stays as it is, commercial interests will govern precision medicine, and patient interests will suffer because in-house personalized testing will not be possible.
Let us keep the flexibility and creativity alive
Standardization is fine if you want to mass produce a car, but not if you suddenly need to find a creative solution to novel problems in patient diagnostics (as part of precision medicine) or pandemic control (to enhance covid-19 test capacity). The ability to rapidly repurpose testing was crucial to obtain pandemic control in Europe, and here Europe had an advantage over the more rigorous US system. Let us not lose this capacity because a too rigorous IVD Regulation becomes EU law. That would really be a threat to public health.
On behalf of the Executive Board of the European Society of Human Genetics
Gunnar Houge MD PhD
We present, on behalf of EuroGentest and the European Society of Human Genetics, guidelines for the evaluation and validation of next-generation sequencing (NGS) applications for the diagnosis of genetic disorders. The work was performed by a group of laboratory geneticists and bioinformaticians, and discussed with clinical geneticists, industry and patients’ representatives, and other stakeholders in the field of human genetics. The statements that were written during the elaboration of the guidelines are presented here. The background document and full guidelines are available as supplementary material. They include many examples to assist the laboratories in the implementation of NGS and accreditation of this service. The work and ideas presented by others in guidelines that have emerged elsewhere in the course of the past few years were also considered and are acknowledged in the full text. Interestingly, a few new insights that have not been cited before have emerged during the preparation of the guidelines. The most important new feature is the presentation of a ‘rating system’ for NGS-based diagnostic tests. The guidelines and statements have been applauded by the genetic diagnostic community, and thus seem to be valuable for the harmonization and quality assurance of NGS diagnostics in Europe.
ESHG calls for prudent use of WGS-based testing
Van El CG1 & Dondorp WJ4, De Wert GMWR3,4, Cornel MC1,2,3 (on behalf of the ESHG Public and Professional Policy Committee)
(1) Section Community Genetics, Department of Clinical Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands
(2) Center for Medical Systems Biology, Leiden, the Netherlands
(3) Centre for Society and the Life Sciences, Nijmegen, the Netherlands
(4) Department of Health, Ethics and Society; Research Schools CAPHRI & GROW, Maastricht University, Maastricht, the Netherlands
In their Policy Forum contribution Patient autonomy and incidental findings in clinical genomics Susan Wolf et al. criticize the American College of Medical Genetics (ACMG) for giving up on well-established principles of patient autonomy and informed consent. The European Society of Human Genetics (ESHG) recently also called for more prudence. The ACMG presents WGS-based diagnostic testing as an opportunity for screening. The ESHG position is that whenever possible, such testing should be targeted to genome regions linked to the indication. Wider testing requires a justification in terms of necessity and proportionality. Adding screening targets to a diagnostic test violates the necessity criterion. Imposing this extra testing upon patients who need an answer to their clinical problem is at odds with respect for autonomy. As stated by Wolf et al., people have a right to decline testing on the basis of their own assessment of burdens and benefits. However, with regard to reporting unsolicited findings, the ESHG does acknowledge that the patient's ”˜right not to know' may sometimes have to give way to professional responsibilities with regard to the interests both of the patient himself (who may not have foreseen and considered a specific finding) and of his close relatives (”˜duty to warn'). Where testing of children is concerned, the child's best interest may override the parental ”˜right (not) to know'. Pending further debate, we urge a more cautious attitude specifically including the patients' and physicians' perspectives.
 S.M. Wolf, G.J. Annas, S. Elias. Patient Autonomy and Incidental Findings in Clinical Genomics. Science 340,1049 (2013).
 C.G. van El et al. Eur J Hum Genet., 21, 580 (2013).
 W. Dondorp, B. Sikkema-Raddatz, C. de Die-Smulders, G. de Wert, Hum Mutat., 33,916 (2012).
In a letter published in the journal Science on 30 August, Professor Martina Cornel, chair of the Professional and Public Policy Committee of ESHG and colleagues call for restraint in the use of diagnostic testing based on whole-genome sequencing. Wherever possible, such testing should be restricted to those genome regions linked to the patient's indications, they say, and wider testing needs to be justified in terms of necessity. Adding additional targets to a diagnostic test would be a violation of this, they say.
However, in the case of unsolicited findings, the patient's right not to know may sometimes have to be secondary to clinical geneticists' professional responsibilities, say the authors. The patient may not have foreseen a specific finding and in some cases the physician will have a moral duty to warn close relatives. Pending further debate, a cautious approach continues to be warranted, they say.
Letter in Science (for subscribers only)
The letter by Carla van El et al summarises the Recommendations of the ESHG concerning on Whole Genome Sequencing in Health Care (Recommendations and Background Document) published in the European Journal of Human Genetics