Patient relevance: A comment from a legal perspective

"Patient relevance" is a legal term from the law governing the benefit assessment of pharmaceuticals. The law governing the benefit assessment of pharmaceuticals has its parliamentary basis in Section 35a of the Social Code (SGB V) and is further specified by subordinate standards and procedural regulations of the Federal Joint Committee (G-BA). While pharmaceutical approval primarily concerns patient safety and the efficacy of pharmaceuticals, the pharmaceutical benefit assessment forms the basis for the pricing of pharmaceuticals with new active ingredients (cf. Section 130b of the SGB V, Section 78 (3a) of the German Medicines Act (AMG). The pharmaceutical price or reimbursement amount should be benefit-adequate in relation to an appropriate comparator therapy.

The legal concept of patient relevance can be found, among other things, in the following regulations: According to Section 2 Paragraph 3 of the Ordinance on the Benefit Assessment of Medicinal Products pursuant to Section 35a Paragraph 1 SGB V for reimbursement agreements pursuant to Section 130b SGB V (AM-NutzenV), “the benefit of a medicinal product […] is the patient-relevant therapeutic effect, in particular with regard to improving the state of health, shortening the duration of illness, prolonging survival, reducing side effects or improving the quality of life.”

According to Section 5, Paragraph 5, Sentence 1 of the AM-NutzenV, the "additional benefit compared to the appropriate comparator therapy is determined as an improvement in the influence of patient-relevant endpoints for the benefit pursuant to Section 2, Paragraph 3" of the AM-NutzenV. According to Section 35a, Paragraph 3b, Sentence 4 of the SGB V, the Federal Joint Committee (G-BA) is responsible for "determining specifications [...] regarding patient-relevant endpoints and their recording" for the data collection and evaluation accompanying the use of the medicinal product.

Scope for assessment and reasonableness control

The application of the law essentially concerns the question of whether a specific, individual fact (e.g., an improvement in progression-free survival proven by studies) is covered by an abstract, general legal term (e.g., "patient-relevant endpoint"). Legal practitioners speak of whether the fact can be subsumed under the law. This simply means the question of whether the legislator, with its legal norm, actually intended to regulate the fact before the legal practitioner's eyes. The courts have the final, binding decision on such a question.

However, the courts' jurisdiction is limited if the law—which is rare—grant an authority discretion such that, in relation to the court, the authority itself has primary authority to assess whether the facts of the case are consistent with the law. Such discretion is called discretionary power. Where discretionary power is affirmed, the court will examine whether the authority has complied with the jurisdictional, procedural, and formal requirements, has based its decision on the correct facts, and has not considered irrelevant considerations. Otherwise, however, it will only conduct a review of reasonableness.

"Patient relevance" is a so-called indeterminate legal term. Indeterminate legal terms are those legal terms that are highly open to interpretation, difficult to grasp due to their lack of specificity, and involve complex evaluations, assessments, and considerations. Examples of these are legal terms such as "suitability," "particular hardship," or "defacement of the landscape." Unlike purely descriptive legal terms (such as "dog," "cat," or "mouse"), with indeterminate legal terms, the question of whether a real-life situation falls under the legal term cannot be answered at first glance. Indeterminate legal terms are a potential gateway for affirming the discretionary power granted to the authority by the legislature.

In the context of the benefit assessment of pharmaceuticals, the Federal Social Court (BSG) recognizes scope for assessment. Benefit assessment decisions are classified by the BSG as acts of subordinate statutory standard-setting. This follows from the legal nature of the Federal Joint Committee's Pharmaceuticals Directive (Section 92 (1) Sentence 2 No. 6 of the Social Code Book V), of which the benefit assessment decisions become a part (Section 35a (3) Sentence 7 of the Social Code Book V). The scope for assessment is derived here from the freedom of design granted to a standard-setter. This means that social court review may not substitute its own assessments for those of the Federal Joint Committee (see BSG, judgment of August 12, 2021 - B 3 KR 3/20 R = BSGE 133, 1 para. 33). However, this restriction only applies to the extent that the Federal Joint Committee's assessment is justifiable (justifiability review).

Limits of justifiability

Where do the limits of the justifiability of an answer to the question of whether a specific endpoint should be subsumed under the statutory term “patient-relevant” lie? An assessment that qualifies an endpoint recognized in higher-ranking law (in particular SGB V, AM-NutzenV) as not patient-relevant would be untenable. Section 2, Paragraph 3 and Section 5, Paragraph 2, Sentence 3 AM-NutzenV contain so-called standard examples, i.e. explicitly but not exhaustively named factual constellations that, in the opinion of the legislator, should generally be subsumed under the statutory term. In this case, these are the endpoints health status/morbidity, duration of illness/morbidity, survival/mortality, adverse effects, and quality of life. It follows that the question of whether a controversial endpoint is relevant in the context of the benefit assessment can also be decided politically by the legislature or regulatory authority.

Is it sufficient for justifiability – provided no contradiction with higher-ranking law can be established – that it is justifiable according to the relevant sciences (especially medicine) to classify a certain endpoint as not relevant to the patient? If this question were answered in the affirmative, it would be sufficient for the G-BA to find serious opinions for its assessment, even if these contradict the predominantly held view in science (“prevailing opinion”). According to the correct opinion, there is no justifiability in the context of the benefit assessment of an assessment by the G-BA that contradicts the generally accepted state of the art in HTA science. This opinion can be derived, among other things, from Section 35a Paragraph 1 Sentence 8 No. 2 SGB V and Section 7 Paragraph 2 AM-NutzenV.

According to these provisions, the international standards of evidence-based medicine and health economics form the basis of the benefit assessment. The benchmark for the assessment within the framework of the benefit assessment is the generally accepted state of medical knowledge. Therefore, in addition to the statutory standard examples, endpoints recognized as patient-relevant according to international standards must also be recognized as patient-relevant by the Federal Joint Committee (G-BA). In my opinion, this also includes endpoints recognized according to international standards as a meaningful surrogate for a patient-relevant endpoint (mentioned in the law or another internationally recognized endpoint).

With regard to surrogates, however, previous decisions of the Federal Social Court (BSG) and the Berlin-Brandenburg State Social Court (Landessozialgericht Berlin-Brandenburg), which is the first-instance court responsible for the G-BA's benefit assessments (between 2011 and 2013), often state that studies that formulated mere surrogate parameters as their primary objective are not considered to demonstrate therapeutic improvement from the outset (most recently, BSG, judgment of September 17, 2013 – B 1 KR 54/12 R = BSGE 114, 217, para. 48; most recently, LSG Berlin-Brandenburg, judgment of June 7, 2013 – L 7 KA 164/09 KL, juris para. 126). This categorical exclusion has likely been tacitly abandoned by now.

Possible impulses from Union law

Impulses for the justifiability of the assessment of an endpoint's patient relevance can also arise from the European Health Benefit Assessment (EU-HTA). Methodologically, a binding impulse could emerge as a result of an interpretation and application of national law that conforms to EU law (AM-NutzenV). Alternatively, such an impulse could also develop below the strict binding nature resulting from the primacy of EU law, in such a way that the recognition of an endpoint as patient-relevant within the framework of the EU-HTA is viewed by national case law as proof or strong evidence that the endpoint is patient-relevant – according to international standards of evidence-based medicine and health economics or according to the recognized state of medical knowledge.

However, both impulses would likely require a further development of the current EU HTA process. However, even today, under Regulation (EU) 2021/2282 on Health Technology Assessment, it is not entirely impossible that the ECJ could grant some kind of spillover effect under EU law on national assessment procedures for the determination of the relevant parameters for the assessment scope (including health-related endpoints) within the framework of joint clinical assessments, even though such spillover effect is currently not politically desirable according to the official classifications of the scope of Regulation (EU) 2021/2282.

Clarification of patient relevance in legal proceedings

In principle, the patient relevance of an endpoint can be clarified through legal proceedings. Benefit assessments by the Federal Joint Committee (G-BA) that wrongfully (although there is scope for assessment!) disregard a patient-relevant endpoint for which an improvement has occurred based on the study data are unlawful. Unlawful adverse benefit assessments can be challenged by a pharmaceutical company through legal action (responsible courts: Berlin-Brandenburg Regional Social Court (LSG) and the Federal Social Court (BSG). This challenge can be made within the framework of a challenge to an arbitration award concerning the reimbursement amount pursuant to Section 130b Paragraph 4 of the Social Code Book V (SGB V). In this case, the challenge to the arbitration award is combined with an additional application for a declaration of invalidity of the G-BA benefit assessment decision underlying the arbitration award.

Alternatively, a declaratory action directed solely against the benefit assessment decision, with the Federal Joint Committee (G-BA) as defendant, is also possible if, despite the differences in the benefit assessment, a mutual agreement on a reimbursement amount has been reached between the pharmaceutical company and the National Association of Statutory Health Insurance Funds. As far as we can tell, there have been no court proceedings to date explicitly pursuing the goal of establishing an endpoint as patient-relevant.

Conclusion

Patient relevance is an indeterminate legal term with discretionary power in favor of the Federal Joint Committee (G-BA). By assuming discretionary power and the associated reduced judicial review in the form of a mere review of justifiability, case law and legal scholarship throw the ball back into the playing field of medicine, health economics, and other HTA sciences.

The dispute over whether a particular study endpoint is patient-relevant or not is therefore less due to insufficient legal foundation. Rather, the problem stems from the fact that the qualification of a particular study endpoint as patient-relevant is controversial among representatives of the relevant HTA sciences. As long as this is the case, the G-BA's refusal to recognize the patient relevance of an endpoint remains justifiable and lawful.