Genetic biomarker tests for targeted treatment: regulatory and reimbursement challenges in Europe

22 Αυγούστου 2024

MYO Health - Maria Antonaki, Katerina Pilou

According to the Biomarkers Definitions Working Group, biological markers (biomarkers) are “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”.¹As such, biomarkers may be used for diagnostic, prognostic or predictive purposes.²As diagnostic tools biomarkers intent to identify patients with a particular disease or condition.² As prognostic tools they intent to predict the course of the disease regardless of the therapy patients are treated with, whereas as predictive tools they intent to predict patient’s response to a specific treatment, compared to the standard of care, placebo or mere observation.² Although biomarkers encompass a wide range of study fields, for the purposes of this review we will concentrate on genetic biomarkers.

Genetic biomarker tests allow for the optimization of treatment decisions and greater individualization of care and they are key to precision medicine.³Indicatively, the use of next-generation DNA sequencing in clinical oncology has enabled the detection of numerous genomic biomarkers which are common among different cancer types, contributing to a better understanding of the molecular basis of cancer, as well as the prediction of patient’s response to targeted therapies.^4,5It has been estimated that more than 25% of cancer patients can receive individualized treatment based on biomarker test results.⁶

As a key element to precision medicine, biomarker tests offer great value to the healthcare system by identifying patients who may benefit the most, reducing side effects, avoiding suboptimal treatment and, hence, improving patient outcomes, increasing the efficiency of resource allocation and achieving more effective treatment and increased life expectancy.

Many barriers hindering access to high-quality biomarker testing across European countries have been identified. Without adequate access to biomarker testing, the full potential of precision medicine can’t be unraveled. In this context, the reimbursement of biomarker tests is essential in order to reduce uncertainty for patients, increase response to treatment and reduce the side effects that are associated with particular treatments. Despite the fact that in Europe reimbursement policies impact the accessibility of patients to healthcare, they frequently do not facilitate the synchronization of reimbursement decision-making.⁷For example, in Europe decisions on the reimbursement of biomarkers (e.g. companion diagnostics) and their associated targeted therapies are not taken simultaneously and a targeted treatment may receive reimbursement long before the respective companion diagnostic test.^8,9,10This can be attributed to differences in legislation, Health Technology Assessment (HTA) practices, as well as to adherence to different timelines.¹¹

Reimbursement framework of in vitro diagnostics in the EU

Reimbursement procedures for biomarker tests often fall under the general umbrella of in vitro diagnostics (IVDs). In general, reimbursement decision-making varies among European countries in terms of timing and place and in most countries, it follows more decentralized procedures compared to pharmaceuticals.^8,9,10 Many European countries have specific reimbursement procedures tailored to IVDs that are performed in outpatient settings, which usually follow a fee-for-service model.¹²The reimbursement landscape of 8 selected European countries are presented in Table 1. In most of those countries there are strict criteria for inclusion in the benefit basket of each country, usually related to the efficiency and effectiveness of the IVDs.⁷ Italy is in the process of developing a national HTA pathway for genomic technologies, although it has not been implemented yet.¹³

LorAlternative reimbursement approaches for companion diagnostics

Although procedures for the reimbursement of in vitro diagnostics commonly also apply to biomarker tests, some countries have defined alternative procedures for such technologies. Govaerts et al. (2020) reviewed the reimbursement procedures for biomarker testing in 8 European countries (Belgium, Italy, England, Germany, France, The Netherlands, Switzerland and Spain) and identified alternative reimbursement practices for companion diagnostics.⁷ Alternative reimbursement practices for companion diagnostics were reported for Belgium, France and Germany.⁷ In Belgium, the joint assessment, and reimbursement decision-making of molecular diagnostic medical acts and their associated medicinal products was enabled through a royal decree of 2019.⁷ The decree foresees an annex in the benefit basket with biomarkers which are eligible for reimbursement. The annex is updated regularly and in line with the corresponding medicines, enabling the joint inclusion in the benefit basket.⁷ In Germany, the joint assessment of companion diagnostic medical act and the corresponding medicines was constituted with a law of 2019 which foresees that decisions on the reimbursement of companion diagnostics should be made simultaneously with the decisions on the reimbursement of medicinal products.⁷ Finally, in France, in vitro diagnostics and companion diagnostics are included in a “coverage with evidence development” list and are conditionally reimbursed provided additional data are collected to validate their efficacy and assess their cost-effectiveness.⁷

Traditional and risk-sharing reimbursement models

Traditional methods

Non-risk-sharing (traditional methods) and risk-sharing (performance-based methods) have been identified as reimbursement models utilized in personalized medicine, notably in biomarkers, and genetic and genomic testing.¹⁴In terms of traditional methods, existing fee-based payment schemes are typically employed to reimburse testing. Companion diagnostics and genetic testing frequently use existing Current Procedural Terminology (CPT) codes due t

o the lack of a dedicated reimbursement code. Moreover, two traditional approaches of reimbursement have been identified for molecular diagnostic tests in EU5 countries. In the former, these tests were incorporated into existing DRGs and negotiated tariffs at the local and national level, whereas, in the latter, they were covered by state, hospital budgets, or pharmaceutical companies.^{15,16,17,18,19,20,21}

Performance-based methods

Coverage with evidence development (CED) is a type of performance-based reimbursement model applied in molecular biomarkers, including genotyping and phenotyping. Under CED, a promising but unproven medical technology is granted provisional insurance coverage. As a consequence, the manufacturer’s success or failure to submit sufficient data will determine whether or not coverage will be provided.^22,23Another performance-based method used for the reimbursement of molecular biomarkers is value-based pricing. The rationale behind this methodology is that interventions with higher levels of evidence and better outcomes result in payments, whilst those with marginal benefit are discouraged from being used. Furthermore, tier rates based on clinical utility might be assigned.^24,25

Finally, the technology-specific coverage framework approach entails developing a coverage framework centered on a single technology.²⁶This framework governs technologies such as next-generation tumor sequencing, with different coverage criteria being recommended based on the number of genes. The primary requirement for tests with 50 or fewer genes is that at least 5 genes be “established,” and the cost of NGTS cannot surpass the entire cost of single-gene testing. Coverage for tests containing more than 50 genes is recommended for six clinical indications, including the new diagnosis of stage IV lung cancer. According to this, if supported by sufficient evidence, off-label therapies as well as standard-of-care drugs may also be covered. The first three months of the therapy are paid for by the drug manufacturer, and payer coverage begins thereafter if favorable outcomes are achieved.

Major barriers to access to biomarker testing

At the EU level, the main barriers to access to high-quality biomarker testing are: 1) limited availability of precision medicine based on biomarker testing due to delays between EMA approval and their reimbursement, 2) delays in the integration of biomarker testing into clinical practice due to unclear HTA assessment approaches, 3) delays in integrating the tests into the standard-of-care due to the diversity of laboratory infrastructure, capabilities and referral pathways, and 5) inconsistent participation of laboratories in quality assurance systems.

A recent study of Normanno et al. (2022) on the access to biomarker testing for precision oncology assessed the reimbursement rates of oncologic biomarkers across Europe.⁶ The study identified limits to the access to single biomarker tests in various European countries such as Slovakia, Romania and Bulgaria, as assessed by patient and lab survey results. Barriers to access to single biomarker tests were also identified in Southern and Eastern Europe due to lower reimbursement levels (Table 2).

In conclusion, while genetic biomarker tests hold immense potential for advancing precision medicine, significant regulatory and reimbursement challenges impede their full integration into healthcare systems across Europe. Despite the clear benefits, the inconsistent and often delayed reimbursement practices across different European countries hinder patient access to these essential diagnostic tools. The variability in HTA practices, coupled with decentralized and fragmented reimbursement procedures, further complicates the landscape. To unlock the full potential of precision medicine, harmonized policies and streamlined reimbursement processes are crucial, ensuring timely access to high-quality biomarker testing and ultimately improving patient outcomes across Europe.

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