>> This sales threshold, like the previous threshold of 50 million euros, refers to the pharmacy sales price and a period of 12 months. The savings that can be achieved through this are estimated at 100 million euros per year in the medium term (Federal Ministry of Health 2022).
As part of the Medicines Market Reorganization Act (AMNOG), there has been a price regulation for new medicines with document protection since 2011. There are special EU legal provisions for orphan drugs with the aim of promoting research, development and marketing of suitable medicinal products by the pharmaceutical industry (REGULATION (EC) No. 141/2000 of December 16, 1999 on orphan medicinal products). Following on from this, special regulations apply to orphan drugs in the AMNOG procedure, which continue the objectives of the European regulation at the national level (Section 35a Paragraph 1 Sentence 11f. SGB V). Germany has by far the highest and fastest availability of orphan drugs in the European Union (Newton, 2022). Several players in the German healthcare system proclaim that the current special status for orphan drugs undermines the AMNOG as a price regulation instrument and, in their opinion, represent the disproportionate costs of orphan drugs resulting from this as a serious problem for the finances of the statutory health insurance.

The aim of the study was to examine the development of population-normalized treatment costs for orphan drugs over time and thus to address the question of whether and to what extent the AMNOG also fulfills its desired price regulation function for orphan drugs. In relation to the overall market, these profitability goals are achieved (Hammerschmidt 2017).
To examine this question, two working hypotheses were developed:
1. The introductory prices of orphan drugs have not increased or increased only slightly since the introduction of AMNOG
2. The AMNOG discounts granted result in savings compared to the situation before the introduction of AMNOG

Since a significant amount of the required historical data was only available from 2005 onwards, only drugs that were introduced in Germany from 2005 were taken into account for the period before the introduction of the AMNOG benefit assessment (ABDATA Pharmadatenservice 2022, LAUER-Fischer GmbH 2022, Schwabe et al. 2005 to 2020 and Ludwig et al. 2021). There are therefore two different observation periods for the study. The period before the introduction of AMNOG (2005 to 2010) and the period since the introduction of AMNOG (2011 to 2021). During the course of the study, these two subsets will be compared in order to be able to make a quantified statement about the development of treatment costs for orphan drugs.
For the analysis, the annual therapy costs (JTK), i.e. the annual costs incurred by treating a patient with the drug, were calculated based on the so-called net selling price at the time of market launch. The net selling price is determined by the selling price of the pharmaceutical company (ApU) less the statutory discounts § 130a SGB V and § 130b SGB V. The price information used for the study comes from ABDATA (ABDATA Pharmadatenservice 2022). By taking legal discounts into account, this is the price that most closely reflects the actual income of the pharmaceutical manufacturer.
According to information from the Federal Joint Committee, the start of the AMNOG procedure was taken into account as the reference date for calculating the price of the medicines. To calculate the JTK, a population-weighted double average of the net selling price, i.e. using the average of the minimum and maximum, was calculated per population and this was aggregated for the drug if there were several populations. A total of four orphan drugs (“Kymriah”, “Yescarta”, “Epidyolex” and “Reblozyl”) were subject to two simultaneous proceedings when they entered the market. In these cases, an average of both methods was formed.
Due to the very long time series of 17 years, the price information has been adjusted for inflation.
The calculation was made in prices for 2021, based on information from the Federal Statistical Office on the consumer price index (Federal Statistical Office 2022), which enables the results to be viewed in real prices.
In order to be able to record the budget impact of a drug, in addition to the price, the number of patients treated with the drug is crucial. The number of patients treated usually correlates with the number of patients for whom the drug was approved or the GKV target population. If an expensive therapy is only indicated for very few patients, the total costs for the statutory health insurance are still manageable. The one-sided, non-population-based view of JTK therefore leads to shortened conclusions with regard to the treatment costs that arise for the statutory health insurance. Therefore, in the present analysis, the JTK are normalized for the size of the GKV target population.
The size of the target population for each newly approved orphan drug was researched for the period 2005 to 2010. Research sources were Pubmed NCBI, Orphanet and the European Medicines Agency. For the period since 2011, the information on the target population in the benefit assessment decisions of the Federal Joint Committee (G-BA) was used, taking into account the day on which the newly introduced drugs were placed on the market. The JTK per patient was calculated using the information from the specialist information (before AMNOG) or G-BA decision (after AMNOG).
The “normalized treatment costs” were determined using the price and number of patients: for each drug at the time of market launch, the JTK was multiplied by the GKV target population. This results in a meaningful size - hereinafter referred to as normalized treatment costs - which is suitable for comparing the costs incurred for orphan drugs in Germany. For drugs with completed reimbursement amount negotiations, the JTK of the evaluated drug after price negotiation were also taken into account.

In the period between 2005 and 2021, a total of 145 orphan drugs came onto the market in Germany (ABDATA Pharmadaten-service 2022, LAUER-Fischer GmbH 2022, Schwabe et al. 2005 to 2020 and Ludwig et al. 2021). However, not all identified active ingredients could be taken into account for further analysis. Four medicines were exempted (“Defitelio”, “Deltyba”, “Lutathera” and “Dinutuximab beta EUSA”). The procedure was discontinued for one drug (“Sirturo”) and suspended for another (“Zolgensma”). In addition, one drug was discontinued (“Zalmoxis”), two others (“Glybera” and “Translarna”) were withdrawn from the market, and another two could not be taken into account due to a lack of price data (“Gliolan” and “Idefirix”). In the case of “Zynteglo”, the withdrawal from the market only took place after the arbitration award, so the active ingredient was included in the population.
For the period 2005 to 2010 (before AMNOG) there is a subset of 43 drugs, for the period 2011 to 2021 (after AMNOG) there are 91 orphan drugs (see Fig. 1). For 80 of these 91, the price negotiation had been completed at the time of the analysis and so the normalized treatment costs could also be calculated for them after price negotiation based on the reimbursement amount.

In a first step, the discounts achieved from the reimbursement amount negotiation were determined for all orphan drugs as part of the benefit assessment. For this purpose, the JTK of each drug was taken into account. The discount results from the price change between the time of placing the product on the market and the price after the reimbursement amount has been negotiated (12 months later). For the calculation, information was used from a database of the IGES Institute (IGES ARA 2022), in which the price development from market access is recorded for all benefit-assessed active ingredients. This made it possible to determine the exact time of the price change for each drug. The population of orphan drugs with completed AMNOG price negotiations as of March 2022 was 80.
Based on these 80 orphan drugs, the average discount from the AMNOG price negotiations was 19.4% (see Fig. 2). The results can be assessed as robust since the median was only slightly higher with a value of 19.9%. “Tegsedi” achieved the highest value with a discount of 48.4%. The smallest discount was for “Esbriet” at 0.4%. This is the first orphan drug to go through the AMNOG process.
Compared to the overall market, the discount achieved was only slightly below the average price discount after the initial assessment: this was 22.1% for all medicines in the period from 2011 to 2020 (Greiner et al. 2022). A value of 26.2% is reported for the period 2011 to 2015 (Hammerschmidt 2017).
As explained in the methodology, the relationship between price and quantity is crucial for assessing statutory health insurance expenditure. The scatter plot in Figure 3 illustrates this relationship for orphan drugs, with the axes shown logarithmically for better visibility. For the orphan drugs brought onto the market since the introduction of AMNOG, there is a negative correlation coefficient of -0.24. Are only medicines with completed price negotiations delivered?
taken into account, the value increases to -0.3. Accordingly, with orphan drugs there is a negative connection between the JTK and the GKV target population. This relationship has increased slightly since the introduction of AMNOG.
This connection becomes even more clear when looking at the mean JTK or mean number of patients in the GKV target population for the different comparison periods. While the average JTK for orphan drugs rose from 94,183 euros (before AMNOG) to 184,647 euros (after AMNOG with price negotiations), the GKV target populations became significantly smaller - the average fell from 4,586 patients before the introduction of AMNOG to 1,897 patients afterwards . The number refers to orphan drugs with reimbursement amount (n = 80). The value decreases to 1,808 (n = 91) if all orphans (including incomplete reimbursement amount negotiations) are taken into account.
Measured against the average size of the GKV target population for orphan drugs, there are clear steps towards even smaller indications or rarer diseases. While the JTK increased in the period after the introduction of AMNOG, there was a simultaneous sharp decline in the number of patients. The result assessment should therefore be carried out with both effects in mind.
This exact interaction becomes apparent when analyzing the mean normalized treatment costs. The average of the normalized treatment costs before the introduction of AMNOG is used as an anchor value. Without taking inflation into account, their average value rose by 5% at launch in the post-AMNOG period. If the reimbursement amount is taken into account, there is a decrease of 13% (see Fig. 4).
When inflation is taken into account, the effect is even more pronounced (Fig. 5). Accordingly, the inflation-adjusted normalized treatment costs for orphan drugs have decreased since the introduction of AMNOG, both in terms of the introductory price and the reimbursement amount. The mean treatment costs after the introduction of AMNOG are on average only 91% of the original level of normalized treatment costs. If the normalized treatment costs are considered after AMNOG introduction and price negotiation, the value drops to 76%. There was therefore a decrease of 24% compared to the mean normalized treatment costs before AMNOG introduction.

Based on the mean normalized treatment costs, both working hypotheses can be confirmed. Taking into account the size of the target population, the costs for orphan drugs in Germany have not increased on average since the introduction of AMNOG, but have decreased by 9%. If the negotiated AMNOG reimbursement amounts are taken into account, the normalized treatment costs after the introduction of AMNOG are significantly lower than before (minus 24%). Without adjusting for inflation, there has been an increase of 5% since the introduction of AMNOG, which is well below the increase that would be expected if the actual consumer price index for the period were taken into account. If the AMNOG rebates are taken into account, there was a decrease of 13% without adjusting for inflation.
The analysis therefore shows that the AMNOG also fulfills its function as a price regulation instrument for orphan drugs using the orphan privilege. <<