Les Cahiers : En tant que médecin généticien, avez-vous été associé au processus de décision concernant l’utilisation du DPNI en première intention en Belgique ? Quels en étaient les grands déterminants ?

Joris Vermeesch : Yes, I was consulted in and involved in the decision-making process to provide Noninvasive prenatal screening (NIPS) as a first-tier screening test in Belgium. This has been a lengthy process.

NIPS was offered to all pregnant women in Belgium starting 2013. At that time, the costs for the test had to be paid out-of-pocket, which means by women themself. Obviously only a small subset of pregnant women were able to do so. The main users were older women with an overall increased risk for trisomy 21. In the next years, different insurers started offering partial reimbursement for the test. Together with reductions in the overall costs, more and more women opted for NIPS. With this partial reimbursement and unequal access for women, pressure was building upon the government to investigate a potential reimbursement of NIPS.

The government asked the Belgian Health Care Knowledge Center (KCE) to evaluate the health economic consequences of the introduction of NIPS as a first or second tier test. At that time, biochemical and ultrasound first- and second-trimester screening for trisomy 21 (T21) was reimbursed for all pregnant women in Belgium. Using a cut-off risk of 1:300 for T21, about 5 % of all pregnant women were referred for definitive prenatal diagnosis using an invasive test, at a sensitivity of (only) 72,5 %. At this time, about 83 % of pregnant women were screened for trisomy 21 risk.

1 Quality Adjusted Life Year. The QALY is commonly used in health economic evaluations as a means o (...) 2 F. Hulstaert, M. Neyt, W. Gyselaers, The non-invasive prenatal test (NIPT) for trisomy 21 – healt (...) 5A cost-consequences analysis was performed by KCE, presenting the impact on benefits, harms and costs. Context-specific real-world information was available to set up a model reflecting the screening situation in Belgium at that time. This model was used to construct the second and first line Noninvasive prenatal test (NIPT) screening scenarios applying information from the literature on NIPT test accuracy. The sensitivity and specifity of NIPS were shown to be over 99 % for T21. In contrast with NIPS in the second line, offering NIPS in the first line additionally would have missed fewer cases of T21 due to less false-negative test results. In 2014, the time when the study was performed, the costs for a NIPS test was 460 €. The introduction of NIPS in the second line would have resulted in cost savings. If NIPT had been offered to all pregnant women, the price should have been lowered to about 150 € to keep the screening cost per T21 diagnosis constant. However, the model did not take into account the effects of screening for trisomy 13 and trisomy 18. In addition, the model did not take into account the long term medical and care costs of caring for patients with T21. This long-term horizon to translate outcomes to incremental cost-effectiveness ratios expressing the results per (QA)LY1 gained was not applied. Nevertheless, the KCE recommended the introduction of NIPS as second tier screening test and, only when costs would reduce further, as a first tier screening test2.

3 Arrêté royal du 15 octobre 2017, Moniteur belge, 25 nov. 2017, p. 96021. 6Based on those recommendations, the ministry of health wrote in 2017 the law stipulating the reimbursement for NIPS as a first tier test in Belgium3. Reimbursement was set at 260 € per test, well below the costs in other EU countries. The rationale for this lower costs was based on the competitive price offered by both the university laboratories and the commercial offerings in Belgium in 2017.

Les Cahiers : Cinq ans après l’entrée en vigueur de la nouvelle réglementation belge, estimez-vous que le DPNI constitue un des grands succès de la médecine génomique ? Pouvez-vous préciser cette affirmation ?

4 E. Van den Bogaert et al., « Outcome of publicly funded nationwide first-tier noninvasive prenata (...) 8Joris Vermeesch : The outcomes of the implementation of NIPS on the general population in Belgium were clearly established by a collective publication. With a 80 % uptake of NIPS, overall incidence of trisomy 21 was further reduced to 0,04 % of all live births and the overall number of invasive obstetric procedures had been halved4. If you take into account that the reimbursement cost has been further reduced to 240 € per test, the health and health economic consequences of NIPS as a first-tier test in Belgium followed the predictions. In addition, uptake in 2021 has risen to 90 % of the pregnant population.

A benefit for society also lies in the broadened scope of NIPS. Since all neonatal and invasive prenatal genetic testing in Belgium is performed at one of the eight Belgian genetic centers, introduction of NIPS was considered as an opportunity to broaden the scope of traditional prenatal testing by implementing personalized genomic medicine for the obstetric population and as a consequence improved overall prenatal care. Thanks to the implementation in many genetic centers of a « genome-wide NIPS » and the broadening scope in which centers report relevant health actionable findings others than the common trisomies, the test, in my opinion, appears as the major success of genomic medicine and beneficial to society.

As a matter of fact, the Belgian Advisory Committee on Bioethics advised that « secondary findings », i.e. fetal as well as maternal chromosomal anomalies beyond the common trisomies, detected during genome-wide NIPS should be reported when clinically significant21. In case this information may lead to preventive or therapeutic intervention, it is important to share it with the patient and provide genetic counselling. The failure to do so may be construed as serious negligence. This prompted the Belgian Society for Human Genetics to issue guidelines on that matter22. Secondary findings are reported if they are considered technically valid, if there is validated evidence on the associated phenotype and if they are considered clinically relevant and actionable. For example, because of the controversy about the validity and clinical utility of NIPS as a screening tool for fetal sex chromosome abnormalities, they are not reported. On the contrary, when NIPS reveals maternal copy number variations, they are reported if clinically relevant and actionable.

Les Cahiers : Dans le cadre du Centre for human genetics que vous dirigez à l’Hôpital universitaire de Louvain, vous avez développé votre propre test de DPNI et êtes aujourd’hui inquiet de la capacité de laboratoires comme le vôtre à continuer de mettre au point ses propres tests. Pouvez-vous expliquer pourquoi ?

5 B. Bayindir et al., « Noninvasive prenatal testing using a novel analysis pipeline to screen for (...) 12Joris Vermeesch : Research on non-invasive prenatal testing using cell free DNA started in our laboratory in 2005, well before the advent of new sequencing technologies. Following the seminal paper describing the potential of non-invasive prenatal testing by sequencing circulating cell free DNA (cfDNA), we engaged in exploring the potential of this new method. This led us to develop and implement an in-house concieved algorithm to detect fetal trisomies in maternal blood5. The methodology has been shared between Belgian genetic centers and was implemented by all of them.

Since then, it has become the major test in Belgium and allowed for the cost efficient implementation. Together with the reimbursement of NIPS for the general population, testing could be performed at other hospitals and commercial testing sites as well. Those peripheral centers have used the commercial offerings, more precisely the three offers in place : Veriseq (from Illumina), Harmony (from Roche) and Vanadis (from Perkin Elmer). Since all positive NIPS results require an invasive confirmatory test and since all invasive genetic testing is performed in one of the eight Belgian genetic centers, these centers set up a register to monitor the performance of the different tests in Belgium. Between January 1, 2020 and December 31, 2021, Belgium recorded 231 944 live births and 211 066 NIPS tests. About 90 % of all pregnancies opted for NIPS. 437 NIPS led to a subsequent invasive test for trisomy 21. Overall positive predictive values for non-invasive trisomy 21 detection was respectively 75 % for VeriSeq, 90 % for Harmony, 59 % for Vanadis and 94 % for the in-house test developed by the genetic centers (unpublished results). Hence, it appears that the in-house developed test slightly outperforms current commercial testing with both a lower false positive rate and a lower number of tests without a result.

While we show that in-house developed tests can compete with commercial offerings and while we believe that they can complement and drive product improvement for companies, the future of laboratory developed tests in Europe is in peril, which will probably hamper European competitiveness in health care innovation. This innovation faces two main challenges.

6 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical (...) 15A first one is the new Medical devices and in vitro diagnostic regulation (IVDR) issued in May 2017 and came into force on May 26 20216. The priority of this regulation is to ensure a robust, transparent and sustainable regulatory framework and maintain a high level of safety for medical devices and in vitro diagnostics, while supporting innovation. Genetic testing devices like NIPS are entailed by this new regulation. Not only companies, but also individual laboratories creating novel tests must fulfill the requirements of the new IVDR. The implementation of laboratory developed tests remains possible, but requires a number of criteria to be fulfilled : (1) for any test, there should not be an equivalued in vitro diagnostic approved product on the market; (2) if the laboratory developed test is an improvement over any IVDR commercial offering, the arguments and proof for non-equivalence has to be provided to and approved by a national body that overviews approval ; (3) the approval of a laboratory developed test requires a substantial amount of new additional administrative work-up. These three criteria will challenge and hamper the development and implementation of novel diagnostic tests in Europe.

Concerning NIPS, individual laboratories will need to prove the performance of their test and provide arguments why their offering does not exist in any company. Although there are many potential arguments to, it remains unclear what the administrative bodies will accept. For example, is an increase in positive predictive value from 75 to 95 % a valid argument to approve a laboratory developed test ? Since there are different commercial offerings and the different offerings have different positive predictive values, how will the equivalence evaluation be done ? As far as KU Leuven is concerned, our in-house test allows the detection of maternal cancers. This is well beyond the scope of the aim of the test, but can clearly be of added clinical value for the pregnant women. Will this argument play in favor of our test ? At this time all that remains uncertain. But equally concerning is the staggering amount of administration that laboratories are required to provide. Individual laboratories nor hospital administrations are prepared to support this administration.

7 N. Hawkins et al., « The continuing saga of patents and NIPT », Prenatal Diagnosis may 2019, p. 4 (...) 17A second challenge is the David versus Goliath relation of independent non-commercial laboratories compared with big companies. Many commercial NIPS tests are protected by patents which aim at ensuring their owners a viable return on investment. Individual laboratories may develop independent and novel approaches, especially university laboratories at the cross-road of technological and medical innovation. Concerning these in-house NIPS, either those methods obviously infringe patents and hence, royalties should be paid ; or they do not infringe patents and the laboratory has freedom to operate. Unfortunately, it’s often not very obvious whether certain methods infringe patents (different experts may provide different opinions). Many patents cover both DNA analysis, NIPS and prenatal care in general. There are many patents held by many parties internationally, with litigation over these patents ongoing in many countries. Importantly, there are significant international differences in patent law, with patents invalidated in the USA that remain valid in Europe. The patent situation about NIPT remains in a state of flux, with uncertainty about how patent rights will be conferred in different jurisdictions, and how patents might affect clinical access. However, the effects on access in public healthcare systems are more complex and need to be monitored7.

Last but not least, a general tendency is that companies, even when there is clearly no infringement, often sue one-another aiming to (temporarily) protect their own interests or even frighten small laboratories. As outcomes of patent related lawsuits are highly unpredictable, individual laboratories and hospitals are ill-placed to engage in juridic quarrels with big companies.

<footnote n="1">1 Quality Adjusted Life Year. The QALY is commonly used in health economic evaluations as a means of quantifying the health effect of a medical intervention.</footnote>

<footnote n="2">2 F. Hulstaert, M. Neyt, W. Gyselaers, The non-invasive prenatal test (NIPT) for trisomy 21 – health economic aspects. Health Technology Assessment (HTA), Brussels, Belgian Health Care Knowledge Centre (KCE), 2014.</footnote>

<footnote n="3">3 Arrêté royal du 15 octobre 2017, Moniteur belge, 25 nov. 2017, p. 96021.</footnote>

<footnote n="4">4 E. Van den Bogaert et al., « Outcome of publicly funded nationwide first-tier noninvasive prenatal screening », Genet Med. 2021, Jun 23(6), p. 1137-1142.</footnote>

<footnote n="5">5 B. Bayindir et al., « Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management », Eur J Hum Genet 2015 Oct., 23(10), p. 1286-93.</footnote>

<footnote n="6">6 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices replaced Council Directive 90/385/EEC on active implantable medical devices and Council Directive 93/42/EEC on medical devices. It should have entered into force on May 2020, but it was postponed due to the Covid-19 pandemic.</footnote>

<footnote n="7">7 N. Hawkins et al., « The continuing saga of patents and NIPT », Prenatal Diagnosis may 2019, p. 441-447.</footnote>