Companion Diagnostics in Germany

Companion diagnostic (CDx) is evaluated and listed in the EBM (Einheitlicher Bewertungsmaßstab) catalogue in Germany, let’s enrich the discussion around each step, focusing on specific mechanisms, scientific rationale, and real-world examples. Here’s a more granular breakdown of each step:

Step 1: Regulatory Approval under IVDR (In Vitro Diagnostic Regulation)

The In Vitro Diagnostic Regulation (IVDR) is the cornerstone for ensuring that a CDx is analytically and clinically validated before entering the market. It introduces stringent clinical evidence requirements, similar to those applied to medicinal products.

Scientific and Clinical Insights:

1. Analytical Validity:
   • Analytical validity addresses the test’s sensitivity, specificity, accuracy, reproducibility, and robustness. Manufacturers are required to conduct method comparison studies, precision studies (both within-run and between-run), and studies on interfering substances (such as haemoglobin, lipids, or other endogenous or exogenous substances that could skew results).
   • Example: In Qiagen’s Therascreen EGFR RGQ PCR Kit, analytical validity was proven by comparing the PCR assay results with traditional sequencing methods like Sanger sequencing. The assay demonstrated superior sensitivity in detecting low-frequency EGFR mutations, which is critical for identifying patients eligible for targeted therapies like Gefitinib.
2. Clinical Validity:
   • Clinical validity requires demonstrating that the biomarker the CDx detects is directly correlated with the therapeutic outcome. For example, in oncology, a CDx must demonstrate that a genetic mutation (like EGFR or KRAS) influences the likelihood of response to a specific targeted therapy.
   • Case Study: Roche’s FoundationOne® CDx underwent rigorous clinical validation by comparing its results with established methods like Next-Generation Sequencing (NGS) and correlating specific mutations with clinical outcomes in trials. This ensured that the test reliably identified mutations associated with sensitivity or resistance to specific cancer therapies.
3. Clinical Performance Studies:
   • Under the IVDR, CDx products must undergo clinical performance studies that include real-world data and clinical outcomes. This can involve retrospective analysis of patient data, prospective clinical trials, or observational studies.
   • Example: For PD-L1 testing associated with Pembrolizumab (Keytruda), clinical performance studies from trials like KEYNOTE-024 demonstrated that patients with higher PD-L1 expression (as measured by Dako’s 22C3 pharmDx assay) had a significant improvement in progression-free survival when treated with Pembrolizumab compared to chemotherapy.

Step 2: Assessment by the G-BA (Gemeinsamer Bundesausschuss)

The G-BA evaluates CDx based on its clinical benefit, aligning with the therapeutic benefit provided by the corresponding medicinal product. This is where the scientific rigor behind clinical utility comes into play.

Scientific and Clinical Assessment Process:

1. Clinical Utility:
   • Clinical utility is paramount in the G-BA’s evaluation process, focusing on whether the CDx improves patient outcomes by altering clinical decision-making. The test must demonstrate that it is not merely diagnostic but essential for choosing the correct therapeutic pathway.
   • Example: The Oncotype DX Breast Recurrence Score® Test revolutionized the treatment paradigm in early-stage breast cancer by providing a gene expression profile that predicts the likelihood of chemotherapy benefit. Clinical trials like TAILORx showed that patients with a low recurrence score could safely forgo chemotherapy, while those with a high score would benefit from it. The G-BA’s decision to reimburse Oncotype DX was driven by this direct impact on treatment decisions.
2. Comparative Effectiveness:
   • G-BA assesses the incremental benefit of the CDx over existing methods. This involves comparative effectiveness research, where the CDx is compared against other diagnostic tools or strategies to assess whether it improves outcomes, reduces adverse events, or enhances patient stratification.
   • Case Study: For Qiagen’s Therascreen EGFR Kit, comparative studies showed that patients identified as EGFR-mutant positive by Therascreen responded better to Gefitinib and Osimertinib compared to patients with unselected EGFR testing methods. This comparative data was key to securing G-BA approval.
3. Health Technology Assessment (HTA):
   • The Institute for Quality and Efficiency in Healthcare (IQWiG) often performs a Health Technology Assessment (HTA) to assess whether the CDx brings additional value in terms of clinical benefit and cost-effectiveness. This involves modelling potential long-term health outcomes using data from clinical trials and observational studies.
   • Example: PD-L1 testing for Pembrolizumab (Keytruda) underwent HTA scrutiny by IQWiG. The testing’s clinical utility was supported by the KEYNOTE-024 trial, which showed that selecting patients based on high PD-L1 expression led to better progression-free survival outcomes. The HTA showed that this stratification avoided the unnecessary use of chemotherapy, leading to a more tailored approach to treatment, improving both patient quality of life and healthcare costs.

Step 3: Application for Inclusion in the EBM Catalogue

Once a CDx passes G-BA assessment, it moves into the EBM inclusion process, where outpatient use is evaluated for its clinical necessity and cost-effectiveness.

Scientific and Economic Insights:

1. Cost-Effectiveness Analyses:
   • Cost-effectiveness plays a major role in determining the inclusion of a CDx in the EBM. Manufacturers must show that using the CDx leads to better long-term health outcomes and that the costs associated with its use are justified by the savings from avoided ineffective treatments or reduced side effects.
   • Example: The Oncotype DX test was shown to be cost-effective in multiple economic models, as it avoided unnecessary chemotherapy in low-risk breast cancer patients, leading to significant savings in chemotherapy-associated costs like hospital admissions for side effects, reduced productivity, and improved quality of life.
2. Budget Impact Models:
   • A budget impact model is typically required to show how the widespread adoption of the CDx would affect overall healthcare costs within the German health insurance system. This involves calculating the expected number of patients eligible for the CDx, the costs of the test, and the anticipated savings from improved treatment decision-making.
   • Example: For Qiagen’s Therascreen Kit, budget impact models demonstrated that accurately selecting patients for EGFR-targeted therapy (Osimertinib or Gefitinib) not only improved patient outcomes but also reduced the costs associated with ineffective treatments and disease progression.

Step 4: Interim Reimbursement Pathways

Before gaining full inclusion in the EBM, CDx can access reimbursement through GOÄ (private billing) or hospital-based NUB (New Examination and Treatment Methods) systems, allowing early market access while collecting real-world data.

Scientific Rationale for Interim Pathways:

1. NUB Funding:
   • The NUB process allows innovative diagnostics like CDx to receive temporary reimbursement in hospitals while they are under evaluation. Hospitals can apply for NUB funding for a specific CDx, enabling clinicians to use the test while gathering real-world evidence (RWE) on its effectiveness.
   • Example: FoundationOne® CDx by Roche initially entered the German market through the NUB pathway. By using NUB, Roche was able to introduce the CDx to hospitals, where it was used to guide treatment decisions in complex cancer cases, while the company continued to collect evidence supporting broader reimbursement.
2. GOÄ Private Billing:
   • For outpatient settings, if the CDx is not yet reimbursed by the EBM, it can still be offered through the GOÄ system, where physicians bill patients or private insurance for the test.
   • Example: Oncotype DX was initially available in Germany via GOÄ before gaining inclusion in the EBM. During this time, physicians could offer the test to eligible patients, ensuring they received personalized treatment while formal reimbursement was under review.

Step 5: Clinical and Economic Evidence Submission

In addition to real-world data, CDx manufacturers must submit detailed evidence showing that their product improves both clinical outcomes and cost-effectiveness.

Deep Dive into Evidence Requirements:

1. Randomized Controlled Trials (RCTs):
   • For inclusion in the EBM, manufacturers often need to submit results from large, multi-centre RCTs demonstrating that the CDx improves patient outcomes when used to guide therapy decisions.
   • Example: The TAILORx trial for Oncotype DX is a prime example. This landmark RCT showed that patients with low-risk recurrence scores (determined by Oncotype DX) had no benefit from chemotherapy, while those with high-risk scores did. This directly informed the treatment decision and became a pivotal part of the test’s reimbursement application.
2. Observational and Real-World Evidence (RWE):
   • Real-world evidence is increasingly important in gaining reimbursement. Manufacturers often submit observational studies showing the impact of CDx use in clinical practice.
   • Example: The use of FoundationOne CDx in clinical practice across multiple tumour types generated RWE that supported its utility in guiding targeted therapy decisions. This data was crucial in justifying its cost-effectiveness to German payers.

Step 6: Final Inclusion in the EBM Catalogue (continued)

Final Decision Factors:

1. Clinical Necessity:
   • The G-BA, in collaboration with the KBV (National Association of Statutory Health Insurance Physicians), must be convinced that the CDx is clinically indispensable for making therapeutic decisions. This means that the test provides actionable information that significantly impacts patient outcomes, specifically for targeted therapies.
   • Example: The inclusion of PD-L1 testing for Pembrolizumab (Keytruda) was driven by data from clinical trials like KEYNOTE-024, showing that patients with high PD-L1 expression had much better outcomes with Pembrolizumab compared to chemotherapy. The clinical necessity of stratifying patients based on PD-L1 expression was critical to justify inclusion in the EBM catalogue.
2. Economic Benefit and Health System Impact:
   • Final approval for EBM inclusion heavily relies on the economic benefits of the CDx. This involves the CDx demonstrating that it reduces overall healthcare costs, either by avoiding unnecessary treatments, preventing adverse events, or improving survival and quality of life, which translates to fewer hospitalisations and reduced use of healthcare resources.
   • Example: Oncotype DX was included in the EBM catalogue after showing that it could prevent chemotherapy in about 70% of early-stage breast cancer patients with low recurrence scores. By avoiding chemotherapy, significant cost savings were realised, both in terms of treatment costs and reducing chemotherapy-related side effects, which lowered hospital admissions and outpatient care costs.
3. Real-World Data and Post-Market Evidence:
   • The G-BA increasingly considers real-world data (RWD) and post-market surveillance as part of the ongoing evaluation of a CDx. Even after initial inclusion in the EBM, ongoing monitoring of clinical effectiveness and economic impact is often required to justify continued reimbursement.
   • Example: For Roche’s FoundationOne® CDx, real-world data collected from hospitals using the test under the NUB pathway provided critical insights into its utility across multiple cancer types. The continuous data feed from real-world applications demonstrated that it could identify actionable mutations beyond those included in clinical trial data, supporting its broader inclusion in the EBM.

Real-World Case Studies Summarized:

1. Qiagen’s Therascreen EGFR RGQ PCR Kit:
   • Therapeutic Area: Non-Small Cell Lung Cancer (NSCLC).
   • Pathway: The Therascreen test underwent stringent regulatory approval under the IVDR, demonstrating analytical and clinical validity for identifying EGFR mutations. It was reimbursed after G-BA assessed its impact on patient outcomes, showing that it accurately identified patients who would benefit from EGFR inhibitors like Gefitinib.
   • Outcome: After being used under the GOÄ system and supported by budget impact models, it was included in the EBM, making it widely reimbursable for outpatient NSCLC management.
2. Oncotype DX Breast Recurrence Score:
   • Therapeutic Area: Early-stage breast cancer.
   • Pathway: This genomic test underwent rigorous clinical validation through trials like TAILORx, proving that patients with a low recurrence score could safely avoid chemotherapy. Economic models demonstrated substantial cost savings, leading to G-BA’s approval for EBM inclusion.
   • Outcome: Initially available through GOÄ billing, Oncotype DX’s inclusion in the EBM was secured based on strong clinical data and cost-effectiveness, significantly impacting treatment decisions in early-stage breast cancer.
3. FoundationOne® CDx:
   • Therapeutic Area: Comprehensive genomic profiling for multiple cancers.
   • Pathway: Roche’s FoundationOne® CDx was first reimbursed under the hospital-based NUB pathway, allowing its use while gathering real-world evidence. It demonstrated its clinical utility by identifying actionable mutations across various cancer types, leading to better-targeted therapies.
   • Outcome: The G-BA evaluated FoundationOne CDx for inclusion in the EBM after gathering real-world data that supported its use in a broad range of cancers. Its eventual inclusion was supported by its cost-effectiveness in guiding personalised treatment regimens.

Conclusion

The process of getting a brand-new companion diagnostic (CDx) listed in Germany’s EBM catalogue is rigorous, with each step requiring strong scientific and clinical evidence. From regulatory approval under IVDR to economic models proving cost-effectiveness, manufacturers must demonstrate that the CDx significantly improves patient outcomes and reduces healthcare costs. Real-world evidence, either collected through interim pathways like NUB or private billing via GOÄ, can provide critical support for EBM inclusion. Success stories like Oncotype DX, Therascreen EGFR, and FoundationOne CDx illustrate how a combination of robust clinical data and strategic reimbursement pathways leads to full market access and reimbursement in Germany.