The Evaluation of Orphan Drugs by the German Joint Federal Committee—An Eight-Year Review

According to estimates by the German National Action League for People with Rare Diseases (Nationales Aktionsbündnis für Menschen mit Seltenen Erkrankungen; NAMSE), four million people in Germany have a rare disease. A disease is considered rare in the European Union if no more than five in 10 000 people are affected (www.namse.de). Despite the Regulation (EC) No. 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products, there is no adequate drug treatment for many rare diseases. Since 1 January 2011, an (additional) benefit assessment for all newly approved drugs must be presented to the German Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA); based on this, drugs are then assigned to one of six additional benefit categories (table). Some special rules apply to orphan drugs (OD) used to treat rare diseases. A main difference to the regular assessment is that, when assessing the benefits of ODs, the legislature specifies that the additional medical benefit has already been proven by the approval. Therefore, the additional benefit categories of “no additional benefit” and “less benefit” are omitted for ODs (table). Furthermore, for ODs, an additional benefit does not have to be proven by comparison to an appropriate comparative therapy that had been previously approved by the G-BA.

Table. Categories of additional benefits.

Major additional benefit	Sustainable and not-yet achieved large improvement of the therapy-relevant benefit: – healed – considerable increase of overall survival time – long-term absence of serious symptoms – substantial avoidance of severe adverse effects
Considerable additional benefit	Not-yet achieved significant improvements of the therapy-relevant benefits: – reduction of serious symptoms – moderate increase of overall survival time – notably reduction of disease – relevant avoidance of severe side effects, or important avoidance of other adverse effects
Minor additional benefit	Not-yet achieved moderate, but not merely marginal, improvements of the therapy-relevant benefits: – reduction of non-serious symptoms – relevant avoidance of adverse effects
Non- quantifiable additional benefit	Scientific data do not allow any quantification
No additional benefit	No additional benefits are proved	Neither category applies to orphan drugs (as the legislator has specified that additional benefits have already been proven through approval)
Less additional benefit	Benefits of the drug are less than the benefits of the appropriate comparative therapy

In the present study, the key findings of the completed OD procedures are presented descriptively.

Methods

An update of an earlier cross-sectional analysis of completed OD benefit assessment procedures was carried out (1). ODs were included if their assessment had been published by the G-BA in the period from June 2012 to April 2020 (2). Benefit assessments were not taken into account for ODs that exceeded the turnover limit of 50 million euros, had repealed proceedings, or had early termination of proceedings. As procedures that exceed the 50 million euro limit are re-assessed by the Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) and are subject to different assessment rules, these procedures were not included in the present analysis.

Results

Seventy procedures for OD benefit assessments with 81 therapeutic indications were evaluated (Figure a; a detailed table is available on request). More than two-thirds of ODs were used to treat oncological diseases (40%) and metabolic diseases (29%). The cumulative number of patients covered by German statutory health insurance (Gesetzliche Krankenversicherung; GKV) in the target population in Germany was between 62,346 and 120,268 people.

Figure.

Flow chart of (a) the ODs included in the analysis, and (b) their additional benefit classification

OD, orphan drugs; TIs, therapeutic indications

Across all indications, 70 ODs were most frequently (73%) assigned a non-quantifiable additional benefit (for example, for acute lymphatic leukemia [blinatumomab], Merkel cell carcinoma [avelumab]); a minor additional benefit was assigned to 16% (for example, for acromegaly [pasireotide], Duchenne muscular dystrophy [ataluren]), and a considerable additional benefit, to 10% (for example, for amyloidosis [patisiran], multi-resistant pulmonary tuberculosis [bedaquiline]). In the study period, a major additional benefit was only determined in one indication (Nusinersen for patients with 5q-associated spinal muscular atrophy type 1) (Figure b).

At least one randomized controlled trial (RCT) was available for benefit assessment for 70% of the 81 indications; pharmaceutical companies submitted other types of studies for 28%, and no studies were submitted for evaluation for two indications. For those with RCTs, the test drug was compared to an active control for 14 indications (25%), and to placebo for 43 indications (75%). In the 57 indications tested by RCTs, the risk of bias was rated as low in 27 studies, high in 17 studies, and unclear in three studies. In all procedures with non-comparative studies for 24 indications (30%), a high risk of bias at the study level was assumed due to the one-armed study design.

The pharmaceutical companies classified the primary endpoint as patient-relevant for 79 indications (94%). In the G-BA’s benefit assessments, however, the primary endpoint was considered patient-relevant for 26 indications (36%). Differences were often due to the fact that primary endpoints based on imaging procedures or laboratory parameters were rated as non-validated surrogate parameters in the benefit assessments.

Discussion

The effectiveness of a drug is proven at the highest level of evidence through RCTs (3, 4). Overall, there was a high proportion of RCTs (69%) among the OD approval studies. In the cases with no RCT, historical controls were sometimes carried out. When using such controls, however, methodological procedures (e.g. statistical adjustments) could not compensate for study limitations (e.g. structural inequality due to a lack of randomization, or distortions due to data collection at different times) in the investigated indications, so that a non-quantifiable additional benefit was determined for all indications without RCT.

In the future, application-accompanying data collection (anwendungsbegleitende Datenerhebung, AbD) will serve to generate findings on the additional benefits of a drug by collecting care-related data from patients; here, the goal is improve the decision-making basis for assessing the benefit of the drug. Nonetheless, even if application-accompanying data collected prospectively in parallel are of high quality and, if possible, have used a (register) protocol comparable to a study protocol, it can be assumed that the reliability of the conclusions for the objectives of the early benefit assessment is lower than those from RCTs. In order to give data from the AbD an additional benefit, high requirements must be placed on statistical methods for addressing structural inequality and other possibilities of distorting uncontrolled data. With the submission of onasemnogen abeparvovec (Zolgensma gene therapy for spinal muscular atrophy) on 16 July, 2020, the G-BA selected the first active ingredient for an AbD and commissioned the IQWiG to create a concept.

According to a controversial draft ordinance by the European Commission, national benefit assessments (as by the G-BA) could be replaced by European joint assessments in the medium term (3– 5). Some joint assessments of pharmaceuticals have already been carried out as pilot procedures. However, these should be viewed critically in light of the goals of the Reform of the Market for Medicinal Products (Arzneimittelmarktneuordnungsgesetz, AMNOG) and the resulting G-BA perspective of an OD benefit assessment (as for the benefit assessments as a whole). To date, the challenges are diverse and unresolved. This includes the intended parallelization of approval by the European Medicines Agency and benefit assessment, the requirements for a European dossier, the maintenance of currently achieved assessment standards and transparency, and the competencies of the member states of the EU and the Commission.