Analyse von Orphan- Drug-Verfahren in der frühen Nutzenbewertung: RCTs versus best-verfügbare vergleichende Evidenz
Authors:   Takeda, Müller Dr. rer. nat. Gerrit , Fanter Dr. rer. nat. Lena ,   Takeda, Knierim Dipl.-Ges.oec. Julia ,   Takeda
Published: March 2023

For drugs intended to use in rare diseases (orphan drugs), the requirements of the early benefit assessment according to § 35a SGB V (Social Security Code, book 5) pose a particular challenge. The Institute for Quality and Efficiency in Health Care (IQWiG) concludes in his working paper GA21-01 on orphan drugs that have undergone a regular benefit assessment as part of a re-evaluation that the additional benefit of the initial benefit assessment for market access was fictitious. Therefore, in IQWiG’s view, only randomized controlled trials (RCTs) with an appropriate active control arm should be applied for the assessment of the added benefit of orphan drugs. The authors conducted an own analysis based on the database used by IQWiG on 41 orphan drugs. That analysis showed an average of 1,146 days between the initial and regular benefit assessment and that the respective therapeutic settings differ: While almost 66% of the orphan drugs (27/41) had a soloist status at the time of the initial evaluation, approximately 30% (8/27) had lost this status at the time of the re-evaluation. This circumstance alone already reduced the probability of an additional benefit in regular assessments significantly. In 75% of these procedures (6/8), no additional benefit was given. IQWiG also disregarded the fact that the frequency of a disease, especially in the context of orphan diseases, is essential for the feasibility of an RCT. In those benefit assessment procedures where the company had submitted an RCT, the average size of the target population was 2,445 patients, while in those procedures without presented RCT data, it was 471 patients. Of the orphan drug procedures with presented RCT data (30/41), in 10 procedures the comparator arm did not correspond to the appropriate comparator therapy defined by the Federal Joint Committee (G-BA), which was the decisive factor for the outcome of no additional benefit being identified. However, if the comparator matched the G-BA requirement (20/30), an additional benefit was granted in 85% (17/20). In most of these procedures (15/20), a placebo comparator arm was deemed sufficient by G-BA as an adequate implementation of the appropriate comparator therapy. Of note, in the 17 orphan drug assessments with presented RCT data and achieved an added benefit rating in the regular assessment process, the average target population size in the respective indication was 1,650 patients (10/17) when the clinical comparison was conducted against placebo vs. 3,439 patients in those indications where RCT data were generated against an active comparator (7/17). The analysis showed that RCTs are being conducted also in rare diseases when the disease prevalence is relatively high. However, approximately 8% of rare diseases have a prevalence of less than 1 in 1,000,000, meaning less than 80 SHI patients in Germany suffering from those diseases. IQWiG’s claim for comparative RCT-generated evidence for all orphan drugs therefore needs to be put into question (Nguengang Wakap, Lambert et al. 2020). For those small patient numbers in specific rare diseases, the best available comparative evidence should be evaluated carefully for data being eligible to answer the scientific question of the benefit assessment. For the future, joint efforts aiming for developing adequate and acceptable methodologies while acknowledging a higher uncertainty of evidence are deemed necessary by the authors.