Biomarker-based cancer diagnostics: German pricing regulator sets high validation and reimbursement standards for novel diagnostic methods

By: Dr. med. Kokularajah Paheenthararajah, Pia Riemenschneider

On 20 June 2019, for the first time, the German Federal Joint Committee (FJC − Gemeinsamer Bundesausschuss / G-BA), the highest decision-making body of the joint self-government of physicians, dentists, hospitals and statutory health insurance funds (SHI − gesetzliche Krankenversicherung / GKV) in Germany, made the resolution that a specific biomarker-based test to support the treatment decision for or against adjuvant chemotherapy, i. e. after primary surgery, in certain breast cancer patients may be reimbursed by the SHIs. The present resolution is of general importance. The FJC, inter alia, has further specified the validation standards for novel diagnostic methods. The reimburse­ment of various biomarker-based diagnostics for the use in breast cancer treatment is currently under assessment also in other European jurisdictions, partly with a patchwork of different standards and outcomes.

An increasing number of biomarker-based tests which claim to identify those breast cancer patients who will benefit from adjuvant chemotherapy have in recent years also entered the German healthcare market. While such diagnostics can be very expensive (up to approximately 3,000.00 euros per test) and, up until now, have to be paid by the patients themselves, the actual benefit and risks of those tests often remain unclear. As the main grounds of the present resolution of the FJC and the oral consultation proceedings illustrate, the threshold for a positive assessment and reimbursement of novel medical methods can be very high, particularly, in case biomarker-based diagnostics may potentially lead to the complete omission of a necessary standard treatment of a life threatening disease.

Deutsche Zusammenfassung:

Am 20. Juni 2019 beschloss der Gemeinsame Bundesausschuss (G-BA), das oberste Ent­scheidungsgremium der gemeinsamen Selbstverwaltung von Ärzten, Zahnärzten, Kranken­häusern und gesetzlichen Krankenkassen (GKV) in Deutschland, erstmals, dass ein spezi­fischer biomarkerbasierter Diagnosetest zur Unterstützung der Behandlungsentscheidung für oder gegen die adjuvante Chemotherapie, d. h. nach einer primären Operation, bei bestimm­ten Brustkrebspatientinnen von der GKV erstattet werden kann. Der vorliegende Beschluss ist von allgemeiner Bedeutung. Der G-BA hat unter anderem die Validierungsstandards für neuartige Diagnosemethoden weiter spezifiziert. Die Erstattung mehrerer biomarkerbasierter Diagnostika für den Einsatz in der (Brust-)Krebsbehandlung wird derzeit auch in anderen europäischen Ländern geprüft, teils mit unterschiedlichen Standards und Ergebnissen.

Immer mehr biomarkerbasierte Tests, die behaupten, diejenigen Brustkrebspatientinnen zu identifizieren, die von einer adjuvanten Chemotherapie profitieren werden, sind in den letzten Jahren auch auf den deutschen Gesundheitsmarkt gekommen. Während solche Diagnostika sehr teuer sein können (bis zu ca. 3.000,00 Euro pro Test) und bislang von Patientinnen selbst bezahlt werden müssen, bleiben der tatsächliche Nutzen und die Risiken dieser Tests oft unklar. Wie die tragenden Gründe zum vorliegenden Beschluss des G-BA und die mündlichen Anhörungsverfah­ren verdeutlichen, können die Hürden für eine positive Bewertung und Kostenerstattung neuartiger medizini­scher Methoden sehr hoch sein, insbesondere wenn biomarkerbasierte Diagnostika möglicherweise zum gänzlichen Verzicht auf eine notwendige Standardbehandlung einer lebensbedroh­lichen Krankheit führen können.

Background of the resolution of the FJC

According to the main grounds of the resolution of the FJC, approximately 70,000 women in Germany are diagnosed with breast cancer every year, the most common cancer in women. In early stages, the tumour can often be successfully removed by primary surgery. To treat a possible but undetectable metastasis and, thus, prevent recurrence, adjuvant systemic therapy, most frequently in the form of chemotherapy, is normally used following surgical resection. However, not all breast cancer patients actually need adjuvant chemotherapy since they would not have a relapse even without it. For these patients, risks of potential chemotherapy-related harms may be higher than the actual cancer-related harms. Typically, clinical-pathological criteria are used by physicians to decide for or against chemotherapy. Though, in an estimated 20,000 of the annually diagnosed breast cancer patients, the treating physicians alone cannot give a clear therapy recommendation for or against adjuvant chemotherapy on the basis of the established criteria. For this subgroup of patients, several biomarker-based diagnostics claim to help avoiding unnecessary and potentially harmful adjuvant chemotherapy which, however, would be indicated following the established criteria.

Up until now, biomarker-based tests to support the decisions for or against adjuvant chemo­therapy in primary breast cancer patients are not reimbursed by the SHIs where more than 73 million persons are insured. The reason for this is that, according to Sec. 135 para. 1 of the SGB V (German Social Code Book V – Sozialgesetzbuch V), novel diagnostic and treatment methods may only be offered by SHI-accredited physicians at the expense of the SHIs if, inter alia, there is a positive assessment by the FJC as regards therapeutic benefit, clinical necessity and cost effectiveness − also compared to the methods already applied at the expense of the SHIs − in the light of current scientific knowledge in the respective therapeutic field. This means that as long as the FJC has not positively assessed a novel medical method, SHI-accredited physicians are generally not permitted to use such method at the expense of the SHIs. So far, there has not been any positive assessment of the FJC for a biomarker-based test for the concerned diagnostic use.

Content of the resolution of the FJC

Against this background, the FJC has now decided that “biomarker-based tests in primary breast cancer” should be included in the list of diagnostic and therapeutic methods accepted as a medical care service by the SHIs. However, according to the specifications of the FJC in its resolution, the positive benefit assessment is limited to the use of “biomarker-based tests in women with primary hormone receptor-positive, HER2/neu-negative, node-negative and non-metastatic breast cancer using the ‘Oncotype DX Breast Recurrence Score®’ methodology“. This particular test methodology is based on a multigene expression analysis of a panel of 21 genes from a tumour specimen using RT-PCR technique. In contrast to that, as regards the more than ten other biomarker-based tests which were subject to the same assessed proceedings, according to the FJC, there is at present no hint of a benefit or harm to support any decision for or against adjuvant chemotherapy in primary breast cancer based on those tests.

Particularly, the adequate balancing of chemotherapy-related harms against breast cancer-related harms was one of the key issues during the assessment procedure. The benefit assessment of biomarker-based decisions for or against adjuvant chemotherapy was conducted by the FJC mainly on the basis of prospective randomised controlled trials (RCT), the highest grade of evidence. In contrast to that, according to the FJC, only in exceptional cases also non-randomized controlled trials (non-RCTs) may be included in the assessment procedure. However, this would require that such non-RCTs are, for example, of high-quality or show effects of such magnitude that they cannot be regarded as confounding effects. Further­more, it was indicated that also data from prospective-retrospective studies may be included in the assessment, for example data from the analysis of archival tumour tissue from completed RCTs. This would, however, require, inter alia, the existence of a prospective study protocol as regards the use of the archival tumour tissue, the archival tumour tissue has to be representative for the respective study population and must exist for a sufficient amount of patients.

The FJC concluded that, at present, there is adequate prospective evidence only for the benefit of the Oncotype DX Breast Recurrence Score® methodology. Prospective-retrospective data available for the other biomarker-based tests were not regarded as adequate by the FJC. The present resolution of the FJC will enter into force, if the German Federal Ministry of Health (Bundesgesundheitsministerium) does not raise any objection within two months according to Sec. 94 para. 1 of the SGB V (which is only rarely the case).


Extensive research activities are being carried out in Germany and elsewhere to develop novel prognostic and predictive biomarker-based diagnostics for the personalized treatment of various diseases, notably in the field of oncology. Genetic tests and genome sequencing play a key role here. As regards the reimbursement of such diagnostics, in Germany, SHI patients are already entitled to various genetic testing, for example diagnostic, predictive or pharmacokinetic gene testing, given such testing is medically indicted in the individual case. In this context, the present decision of the FJC stands out for several reasons.

First, unlike companion diagnostics in the traditional sense, which aim to provide essential information for the safe and effective use of a certain corresponding drug, the biomarker-based diagnostic positively assessed by the FJC at hand is not related to a particular chemotherapy drug or method. The test rather aims to support the treatment decision for or against adjuvant chemotherapy of a certain group of breast cancer patients in general.

Second, as the present case illustrates, providing adequate clinical data to convince public payers can be difficult in individual circumstances, particularly, when it comes to novel diagnostic methods, the results of which may misguide physicians and patients to omit potentially lifesaving therapies. For such diagnostics, the validation standards applied by the German pricing regulator are very high as basically data from prospective randomised trials are needed for a positive benefit assessment. The focus on prospective data and the level of evidence based on prospective-retrospective data in the present context was highly disputed among the various stakeholders during the oral consultation proceedings before the FJC.

Third, while the benefit assessment pursuant to Sec. 135 para. 1 of the SGB V normally relates to novel diagnostic or treatment methods in general, in the particular case at hand, the positive assessment is limited to a specific biomarker-based test method/product. This was partly criticized during the oral consultation proceedings before the FJC. With the increasing stratification of treatment strategies in some of the most innovative fields of medicine, however, it is to be expected that this trend will rather continue.

On European level, a patchwork of validation and assessment standards can be observed for such biomarker-based diagnostics. For example, while NICE, UK’s pricing regulator, even recommended three biomarker-based tests as options for guiding adjuvant chemotherapy decisions for the concerned breast cancer patients, in France, for the same diagnostic field, no biomarker-based test was positively assessed by the national authority for health HAS due to the lack of adequate evidence. The biomarker-based diagnostics assessed by these regulators were for the most part identical with the tests assessed by the German FJC. The different outcomes show the complexity and difficulty of the assessment of novel medical methods.