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Germany to Test Genomics-Based Precision Medicine for Cancer, Rare Disease in National Pilot Project


NEW YORK – Germany is embarking on a large-scale national pilot project to evaluate the utility of genomic sequencing for patients with advanced cancer and rare diseases.

Scheduled to kick off in 2024 and to run for at least five years, with reimbursement from public health insurance, the so-called "model project" (Modellvorhaben) will test how clinical genomic sequencing offered by participating university hospitals can help improve diagnosis, therapy selection, and clinical management of advanced cancer and rare disease patients. In addition, the initiative aims to build a nationwide data infrastructure to analyze clinical and genomic data for patient care and research.

At the conclusion of the project, "the decision has to be made, based on the data that we are gathering, whether this will be included into the general healthcare system or not," said Nisar Malek, director of internal medicine and founder of the Center for Personalized Medicine at University Hospital Tübingen, adding that a pilot project is "a very common scheme for introducing new technology or procedures into the healthcare system" in Germany.

The hope is that once data for tens of thousands of patients have been analyzed, it will become clear whether broad genomic profiling has "a reasonable cost-benefit ratio," said Albrecht Stenzinger, head of the Center for Molecular Pathology at University Hospital Heidelberg. "At the end of the day, the question is how to invest taxpayers' money."

Officially called "Model Project for Comprehensive Diagnostics and Therapy Selection by Means of Genome Sequencing for Rare and Oncological Diseases," the pilot sits under the umbrella of GenomeDE, an initiative launched by the Federal Ministry of Health (BMG) as part of a 2019 national strategy for genomic medicine. GenomeDE brings together stakeholders from existing personalized medicine networks, patient organizations, professional societies, and information technology experts, "with the idea to not duplicate things that are already out there," said Stenzinger.

The pilot project was legally implemented as part of a wide-ranging 2021 law on improvements to the German healthcare system and is now enshrined as article 64e of the legal code (Sozialgesetzbuch V) that covers Germany's public health insurance system. As such, it is referred to by some as "model project genome sequencing 64e."

Organizers expect that 10,000 to 20,000 cancer and rare disease patients could have their genomes sequenced under the new project every year, though it will likely be fewer during the initial ramp-up phase.

Originally, the National Association of Public Health Insurance Funds (GKV-Spitzenverband) was supposed to contract with service providers for the project — university hospitals with existing sequencing infrastructure that met stringent participation criteria — by Jan. 1, 2023, but the deadline was extended until Jan. 1, 2024. Negotiations about reimbursement rates for genomic sequencing and related services are still ongoing. Public health insurance, which covers around 90 percent of the population in Germany, will pay not only for sequencing data generation but also for molecular tumor boards or multidisciplinary case conferences. As of earlier this month, the goal was to sign a contract by the end of the year and to start serving patients in the second quarter of 2024.

The pilot project is not the first foray into genomic medicine in Germany, and existing precision medicine networks for oncology and rare diseases are also involved in the new project. Prior initiatives have garnered reimbursement from individual health insurance funds under so-called selective contracts, but the planned pilot is the first that will provide nationwide reimbursement for broad genomic testing, including whole-exome, whole-genome, and transcriptome sequencing.

"The Modellvorhaben is really going one step further, trying to, if you will, democratize broader genomic profiling and really implementing it in routine clinical care, directly reimbursed by public health insurance," Stenzinger said. "I think that's the major difference here."

While a reimbursement scheme for tumor panel sequencing already exists in Germany, he said, "the way that it can be accessed by the different laboratories is still quite challenging and very much depends on the local scenario." And even though exome sequencing for rare disease patients "is already quite well established in Germany, the next logical step will be going for whole-genome sequencing."

Building on existing personalized medicine networks

Personalized medicine initiatives in Germany go back more than a decade. A 2015 regional initiative in the state of Baden-Württemberg built four Centers for Personalized Medicine (ZPMs) at university hospitals in Tübingen, Heidelberg, Freiburg, and Ulm. In 2020, the project successfully contracted for reimbursement of panel sequencing and molecular tumor boards by regional public health insurance funds in the state, according to Malek, who spearheaded the effort.

Since then, the initiative has expanded nationwide into the German Network for Personalized Medicine (DNPM). According to its website, DNPM currently includes 26 university hospitals across Germany that have so far built 21 ZPMs. "I think it is the central place where personalized medicine in oncology is taking place right now in an organized way, where we have started to create a knowledge-generating system of healthcare for patients with advanced cancers for several years now," Malek said. ZPMs are also certified by the German Cancer Society (DKG), an organization that sets national guidelines for treatment of each cancer type.

In parallel, others have built a network specifically for lung cancer. Since 2010, the Network Genomic Medicine, a regional initiative at University Hospital Cologne, has focused on the implementation of personalized lung cancer therapy into routine care and was able to strike selective contracts with a number of public health insurance funds. With funding from German Cancer Aid (Deutsche Krebshilfe), the initiative expanded in 2018 into the national Network for Genomic Medicine (nNGM) Lung Cancer, adding 14 university cancer centers. Since then, the network has grown to 23 centers in 27 locations across Germany, according to its website, offering next-gen sequencing-based diagnostic testing for advanced lung cancer patients and recommending therapies or clinical trial participation. Testing is done centrally at the Institute of Pathology at University Hospital Cologne, which analyzed about 5,000 patient samples in 2022.

On the rare disease side, a three-year prospective study called Translate-NAMSE that ran from 2017 to 2021, organized by the German National Task Force for Patients With Rare Diseases (NAMSE), explored the utility of exome sequencing and interdisciplinary case conferences, provided by Centers for Rare Disease (ZSEs), to deliver diagnoses to previously undiagnosed rare disease patients. The project, sponsored by the German Federal Joint Committee (G-BA) Innovation Fund, involved 10 ZSEs at university medical centers across Germany as well as two public health insurance funds, with sequencing performed at human genetics institutes of university hospitals in Berlin, Bonn, Munich, and Tübingen. The project enrolled almost 5,700 patients, of whom about 1,600 received diagnostic exome sequencing and almost 500 obtained a genetic diagnosis, according to a MedRxiv preprint published earlier this year.

Following the study, several public health insurance funds have continued to fund exome sequencing for rare disease patients under a selective contract. However, according to Malte Spielmann, director of the Institute for Human Genetics at University Hospital Schleswig-Holstein, that still leaves around 25 percent of patients without access to such testing. Also, the current system excludes hospitalized patients, such as newborns in the neonatal intensive care unit. In addition, he said, whole-genome sequencing is not available to patients with public health insurance, though in some German states, mostly in the south, "other reimbursement options" are available to cover it. "This situation creates a systemic disadvantage for patients in other states," he said, which the new pilot project would resolve.

Reimbursement negotiations ongoing

Meanwhile, negotiations about reimbursement rates under the pilot project are underway between the National Association of Public Health Insurance Funds and the Association of University Hospitals Germany (VUD). "We are very confident that eventually, we'll reach an agreement," Stenzinger said earlier this month, noting that negotiations have been "very constructive and based on trust."

It will be important that reimbursement will cover "the full diagnostic pipeline," he said, which is more than just the cost of sequencing reagents that instrument makers often cite for the proverbial sub-$1,000 human genome. Rather, it also needs to include preanalytics, for example the evaluation of a sample for tumor cell content, nucleic acid extraction, and library construction, as well as the bioinformatics pipeline and results interpretation, including molecular tumor boards and case conferences. "A real, full-cost calculation is required in order to make this work," Stenzinger said, and "the reimbursement needs to be thought of in a way that the institutions can actually perform the sequencing in a meaningful way without losing money."

A total of 13 university hospitals, which had to apply by early 2022, qualified as initial service providers for the pilot project, Stenzinger said. However, the project "is flexible, it is dynamic, so other centers can apply as well, and it's likely that the network will grow" over time, he added. Participating centers had to meet a number of criteria. These included having a human genetics department that is involved in research and an accredited sequencing lab with capacity for at least 500 whole genomes per year. For cancer patients, additional criteria included having a molecular pathology lab that has recently participated in proficiency testing for next-gen sequencing; having recent experience with molecular analyses of at least 350 cancer patients per year by WGS, WES, or large panel sequencing; and having regular molecular tumor boards for at least 250 cases per year. Rare disease centers also had to show that they analyzed genomes or exomes of at least 150 undiagnosed patients per year, and that they conducted at least 50 multidisciplinary case conferences per year.

Pilot project to kick off in 2024

Once the project starts in 2024, eligible advanced cancer and rare disease patients can participate after providing informed consent. Cancer patients "will be primarily patients in last lines of therapy where there is great therapeutic need," Stenzinger said. They don't need to be treated at a university hospital but can also be referred by community hospitals or private practices. After their tumor samples are sequenced at a participating university hospital, the results will be discussed by a molecular tumor board, often conducted virtually, with participation of the referring doctor, in order to find additional treatment options. Treatment can then be administered by the patient's local hospital or doctor. "We are centralizing diagnostics and decision-making, but we are not centralizing treatment," Malek said.

For cancer patients, speed will be of the essence. "We do not have the time for this diagnosis to take months or even longer," Malek said. "It has to be provided within weeks — so our plan is to have comprehensive panel testing for the next two years and then shift towards exome and genome sequencing."

This will likely also involve germline testing, according to Stenzinger, since on the order of 10 percent of cancer patients harbor germline mutations that are potentially clinically important. Also, it will be essential that clinical data is captured on a longitudinal basis to be able to follow a patient's trajectory. "Otherwise, it will just be some TCGA dataset," he said, referring to The Cancer Genome Atlas. "I think the interesting part about this clinical project is the collection of prospective clinical data in order to make connections between outcomes and molecular features, for example."

For rare diseases, patients without a molecular diagnosis need to present to a Center for Rare Diseases at a participating university hospital, where an interdisciplinary expert panel will discuss their case and may recommend them for whole-genome sequencing. The results will then be reviewed by the panel, including the referring physician. "This enables the discussion of variants of unknown significance in an interdisciplinary team and is often associated with re-phenotyping of the patient," Spielmann said, which "eventually leads to more and better diagnoses for patients with rare diseases."

For the time being, genomic data for the project will be generated on Illumina sequencers. "All university hospitals are using Illumina," Malek said. "Some already have the new [NovaSeq] X generation, but most have earlier versions. And I would expect, based on the reimbursement scheme that is now coming, that university hospitals will be investing into sequencing technology, bioinformatics capabilities, storage capabilities, and so on to be part of this."

While the project remains technology-agnostic, Stenzinger said, it will be important to agree on certain standards, both on the wet lab and on the bioinformatics side. "We are running pilots for whole-exome, whole-genome sequencing to have some benchmark" for the participating centers, he said. Any standards "will be kind of a living ecosystem because it might well be that three years from now, we would decide differently on certain things. But we want to ensure that at any given time point, the data that we are generating will be as comparable as possible."

Data from the project will be collected for quality assurance, clinical use, and research. The goal is to use IT infrastructure from existing networks, like DNPM or the Translate-NAMSE project. These will be integrated into a national system that will be governed by the Federal Institute for Drugs and Medical Devices (BfArM), according to Malek. The genetic data will be transferred to the German Human Genome-Phenome Archive (GHGA), an existing national omics database that has seven data hubs across Germany and is part of the European Genome-Phenome Archive (EGA). The clinical data will remain in decentralized data nodes "where it largely doesn't leave the university hospital where it's generated," Malek said. "And these nodes will then talk to each other and will be able to export data for specific questions that are posed by the health insurance funds or individuals that have access to the data."

Setting up a national infrastructure is going to be one of the main challenges of the project, Malek said, as will be establishing large-scale clinical genomic sequencing at numerous university hospitals. In addition, "data protection is a big hurdle for the development and progress of these types of endeavors in Germany, because we have very strict data protection laws, which are also divided between federal laws and state laws," Malek said. "These three things will be the most challenging aspects of this."