NEW YORK (GenomeWeb) – Following changes to the reimbursement catalog of Germany's statutory health insurance system that took effect July 1, next-generation sequencing-based genetic tests are now eligible for coverage for the first time, both for hereditary disease diagnostics and for somatic tumor diagnostics. But a provision that requires pre-authorization of tests analyzing more than 25 kilobases of DNA for constitutional disorders or 20 kilobases of DNA for tumor testing is subject to a lawsuit brought by representatives of insurance carriers and doctors against the German Federal Ministry of Health last month.
Also, diagnostic providers that have been offering NGS-based testing say the new regulations, which exclude testing of circulating free plasma DNA and pharmacogenomic testing, are not going far enough. "It's a move in the right direction," Dirk Biskup, co-CEO of genetic diagnostic lab CeGaT in Tübingen, told GenomeWeb in April. "I don't think it is sufficient, especially this restriction to 25kb," he said. "It's better than what we had, but I don't think it's a good model."
Nicolai Kohlschmidt, president of the Professional Association of German Human Geneticists (BVDH), said in a statement last month that the inclusion of NGS diagnostic tests in the reimbursement catalog represents an improvement in care for children with difficult-to-treat epilepsies, developmental disorders, muscular disorders, and brain structural anomalies, as well as adults with rare and severe diseases. However, many genetic testing services will be reimbursed at lower rates now, amounting in some cases to cuts of more than 50 percent.
Under Germany's publicly funded healthcare system, which covers the majority of the population, non-hospital medical services are reimbursed according to a catalog called EBM (Uniform Evaluation Standard). The EBM assigns each service a certain number of points, which can be translated into a euro amount. The value of a point fluctuates over time, depending on the total healthcare budget available and the number of services provided by all doctors within a certain period, and can differ between regions in Germany.
Each medical specialty is covered by a separate chapter in the EBM, with human genetics services listed in chapter 11 and pathology services in chapter 19. Changes to the EBM are decided by the so-called Evaluation Committee (Bewertungsausschuss), which consists of representatives of the insurance carriers or sickness funds (GKV-SV), and the federal organization of accredited doctors (KBV).
In late March, the Evaluation Committee passed a number of changes to the EBM that affect human genetic services. For a start, it split constitutional genetic disease testing, which remains in chapter 11, from tumor genetic testing, which was moved to chapter 19. Previously, both types of services were covered under the human genetics chapter.
The changes also specify that diagnostic testing for genetic changes is only reimbursable when conducted in tissue or organs — cell-free plasma DNA analysis, which is currently in use or under development in many laboratories for noninvasive prenatal testing and for cancer liquid biopsy testing — is explicitly excluded from coverage, as is gene expression analysis.
In addition, pharmacogenetic testing that looks for the presence of variants that may affect a patient's response to drugs are excluded from coverage.
Importantly, the committee moved away from defining reimbursement for genetic services by test technology, replacing it with descriptions of the tests' goals, irrespective of the method, for example finding a certain type of mutation.
"This is probably the biggest change, that they no longer refer to a certain technology when it comes to applying certain codes," Biskup said.
Some genetic services — including extensive sequencing analyses, companion diagnostics, and tumor genetics — will also be reimbursed separately from the general healthcare budget going forward, so an overall increase of these services will not dilute their point value, according to KBV.
On June 22, the Evaluation Committee passed further changes to the EBM, including a new section on reimbursement of immunogenetic tests, for example in preparation for transplants.
Constitutional genetic testing
Section 11.4 of the updated human genetics chapter of the EBM deals with in vitro diagnostics for constitutional genetic changes. Part 11.4.2 covers a number of specific monogenic diseases, prescribing stepwise diagnostics for these. The list includes diseases such as cystic fibrosis, fragile X syndrome, and hereditary breast and ovarian cancer, and was expanded with additional ones, including Noonan syndrome, Marfan syndrome, and Ehlers-Danlos syndrome.
If stepwise diagnostics does not lead to a molecular diagnosis, sequencing of additional genes can be performed once but needs to be preauthorized by insurance.
Part 11.4.3 of the chapter, which covers syndromes and rare diseases, provides a reimbursement code for sequencing and interpretation of up to 25 kilobases of DNA for diseases that occur with a frequency of 1 in 2,000 or less in the population.
Providers who want to sequence and interpret more than 25 kilobases need to seek insurance preauthorization on a case-by-case basis and have to submit a detailed explanation for the medical necessity of such additional sequencing.
Further, reinterpretation of old data in order to reclassify variants of unknown significance is only reimbursable if it is done at least four years after the initial analysis.
On June 22, the Evaluation Committee decided that the new sequencing codes for syndromes and rare diseases are also applicable to prenatal testing, requiring documentation of medical necessity on a case-by-case basis, until updates to the EBM for genetic diagnostics in maternal care, conception, and reproductive medicine — planned for November 1 — take effect.
Tumor sequencing
Restrictions for somatic tumor sequencing are similar to those for constitutional genetic testing under the new EBM. In vitro diagnostics of genetic changes in tumors are now covered in section 19.4, which permits sequencing of up to 20 kilobases of DNA to look for disease-relevant mutations. Starting April 2017, labs must be able to find tumor mutations with a minor allele frequency of 10 percent or less.
Again, sequencing additional DNA needs to be preauthorized by insurance, and its medical necessity must be documented.
Similar rules apply to tumor genetic testing for drug therapy selection — up to 20 kilobases can be sequenced under one code, and additional sequencing is covered by another code.
Restrictions under dispute
Restricting reimbursement for constitutional disease testing to 25 kilobases is a problem for diagnostic providers who have been offering larger NGS panels or diagnostic exome sequencing. Biskup, for example, said that CeGaT's panels typically run on the order of 500 kilobases to 500 megabases, at least 20 times larger than the EBM's limit.
Even the coding sequences of some single genes exceed the 25 kilobase limit — titin, for example, which is frequently mutated in certain types of muscular dystrophy and cardiomyopathy, has more than 80 kilobases of coding sequence.
Also, it is unclear how readily insurance will grant preauthorization for additional sequencing for constitutional and tumor testing, and the EBM established no criteria for how such decisions should be made.
As a result, the German Federal Ministry of Health objected to the preauthorization requirements, saying that it interferes with the right of doctors to freely decide about therapies and diagnostics for their patients, and that it overreaches the authority of KBV and GKV-SV.
In response, on June 22, KBV and GKV-SV filed a lawsuit with the social court (Landessozialgericht) of Berlin-Brandenburg against the health ministry. While the case is proceeding, the preauthorization requirements remain in effect.
BVHD, the professional organization of human geneticists, said it is "outraged" by the behavior of KBV, which represents all accredited doctors. According to Kohlschmidt's statement, current experience with preauthorization for human genetic services shows that insurance carriers lack the competence to judge the necessity of such services for specific cases. "Numerous pregnant women with abnormal ultrasound results and parents of children with disabilities are denied services without cause and are left alone with their worries and fears," he wrote.
Patient advocacy groups and the BVDH are "vehemently fighting the preauthorization requirement," according to the statement.
Prior to the recent changes to the EBM, testing labs could either run NGS panels as part of research studies or seek insurance approval for reimbursement on a case-by-case basis, "and in 95 percent of cases, they did not approve it," Gabriele Gillessen-Kaesbach, professor and chair of the Institute for Human Genetics at the University Medical Center Schleswig-Holstein in Lübeck, told GenomeWeb in April. Whether or not they will be more willing to preauthorize them under the new regulations remains to be seen, she added.
Biskup said he believes the EBM changes will likely benefit CeGaT overall. "We expect a positive effect, because now we no longer have to do Sanger sequencing for single genes but can offer a panel and can sequence even more than 25 kilobases," he said. "That will make it easier in the future."
The new code for sequencing 25 kilobases of DNA has a point value of about €2,000 to €2,400 ($2,200 to $2,700), he said, and additional preauthorized sequencing has a point value of about €3,000 to €3,500. However, actual reimbursement is often lower than the point value, he added.
"From a clinical point of view, it would make sense to sequence genomes or exomes, and then restrict the analysis to certain panels of disease genes," said Saskia Biskup, CeGaT's other co-CEO and a medical geneticist, who also runs a human genetics practice in Tübingen.
Going forward, her practice plans to continue ordering CeGaT's large NGS panels or exomes, but will initially restrict the analysis to 25 kilobases of sequence. If no diagnosis can be made, the practice will seek insurance preauthorization, or alternatively, offer patients a "rather inexpensive analysis" of the remaining sequence data for an out-of-pocket charge of a few hundred euros or less, Dirk Biskup said.
"We will sequence what is needed and what makes sense from a clinical point of view," he said. "It's still about the patient, we want to help the patient, that's our ultimate goal."
Other diagnostic labs are offering eligible patients participation in research studies where they will undergo panel or exome sequencing that may provide them with a diagnosis. The Center for Human Genetics and Laboratory Diagnostics (MVZ) in Martinsried, for example, is recruiting patients with a number of genetic disorders for the Multiple Integration of Data Annotation (MIDAS) study, which aims to study genotype-phenotype correlations for rare diseases with the goal to improve diagnostic testing results.
Change at last
The July 1 changes to the EBM come after several years of quarrels between providers trying to obtain reimbursement for NGS panels and exomes and insurance carriers denying their claims.
Doctors initially started billing German statutory health insurance for NGS tests under a code that covered sequencing-based testing, which led to an increase in overall testing volume under that code. In response, the Evaluation Committee decided in 2013 that the code only applies to Sanger sequencing tests but not to NGS, halting most of NGS testing.
At the time, the committee said it had established a working group to overhaul the EBM chapter on human genetics by mid-2014 to reflect the state of the art of science and technology, but it postponed that deadline twice, citing the complexity of the matter.
Practices and their affiliated testing labs, meanwhile, reverted to stepwise diagnostics that started with Sanger sequencing. Biskup's practice, through CeGaT, continued to offer patients NGS panel testing free of charge, billing insurance only for the initial Sanger testing.
However, its local health insurance carrier, KVBW, balked at this and refused to pay the Sanger claims, resulting in Biskup's practice suing KVBW last year over unpaid Sanger tests, a case that is still pending.