>> Biopharmaceuticals are preferably used for complex diseases or after previous therapies with proven standard medication. This also applies to their copycat products, the so-called biosimilars. If you split the outpatient SHI market for biopharmaceuticals according to ATC2 classes, the most biologics are prescribed for antidiabetics (A10), with more than 220.6 million DDD. This corresponds to a proportion of 67.7% of all DDD prescribed via biologics in Q3/2020, which is due to the high amounts of insulin for diabetes therapy. The antithrombosis preparations (B01) and immunosuppressants (L04) follow in second and third place, with a more than significant gap, with a share of 7% and 6%, respectively, in the entire biopharmaceutical market. However, the markets for which biosimilars are already available as treatment alternatives differ in some cases from this ranking. Immunosuppressants and the therapy of autoimmune diseases are the first market to be mentioned, with currently 12 biosimilars to three of the five TNF-alpha inhibitors. And what about oncologic drugs? A total of 12 biosimilars to three monoclonal antibodies are currently available in the antineoplastic market (L01). It is not surprising that this market is in second place in terms of the number of biosimilars (products including imports), as genetically engineered and therefore targeted therapies are increasingly being used in the treatment of tumor diseases. Here, the prescription share (according to DDD) of biopharmaceuticals used increased significantly from 18.6% in Q1/2017 to 23.5% in Q3/2020 (source: NVI ZUB, INSIGHT Health).
Patent situation in oncology
More and more patents for biologics in oncology are expiring. As a result, market penetration of biosimilars is continually increasing. After initial skepticism among cancer therapists, biosimilars now appear to be increasingly accepted among prescribers. In particular, the monoclonal antibodies that have been used in oncology since the late 1990s are now gradually losing their patent protection (see Fig. 1). The EMA, which is responsible for the approval of biotechnologically produced imitators in the EU, created a corresponding legal framework in 2012 with the “EMA Guidelines for the approval of biosimilar monoclonal antibodies” that clearly defines the requirements (source: EMA).
Rituximab, the first monoclonal antibody approved for the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukemia, was launched in Germany in 1998. In 2006, the approval for rheumatoid arthritis was expanded - here, however, in a combination with low-dose methotrexate. Rituximab's basic patent expired in March 2013. The first imitator and thus the first biosimilar that could be used in the EU for an oncological indication received approval in February 2017. The EMA has now granted a further five approvals for this substance (source: patent database SHARK, INSIGHT Health).
Trastuzumab was introduced in Germany in October 2000 as the second monoclonal antibody. The drug is indicated for the treatment of breast cancer (metastatic and early stage) and in the treatment of metastatic gastric cancer and lost its patent protection in July 2014. However, the first biosimilar only received approval from the EMA in November 2017. In the following years, a further four approvals were granted and an additional biosimilar was introduced in the EU this year (source: patent database SHARK, INSIGHT Health).
The youngest member of the family of monoclonal antibodies with biosimilar competition in oncology is bevacizumab. Since its market launch in 2006, the substance has been approved in combination with other drugs for the treatment of various tumor diseases. The drug is an angiogenesis inhibitor that inhibits the formation of new blood vessels that tumors need for their growth.
Approval was given for the following indications:
• metastatic breast and colorectal cancer,
• non-small cell lung cancer,
• advanced and/or metastatic renal cell carcinoma,
• epithelial ovarian carcinoma,
• fallopian tube carcinoma,
• primary peritoneal carcinoma and the
• Cervical carcinoma.

Bevacizumab's Supplementary Protection Certificate (SPC) and six-month extension through pediatric trials ended in June this year. The first approval for a biosimilar was granted here before it expired in 2018. Others followed in 2019 and 2020 (source: patent database SHARK, INSIGHT Health). As a result, biosimilars were available as a treatment option immediately after the end of market exclusivity. The introduction of other imitators in oncology is not yet over. The EMA has one approval application for trastuzumab and five biosimilar applications for bevacizumab. According to an analysis of INSIGHT Health's SHARK patent database, the next monoclonal antibody used in oncology will lose its patent protection in 2022.
Regional: Biosimilars in the KV split
Looking at the development of the biosimilar quotas for the three substances listed, an increasingly dynamic uptake can be seen in the chronological order of patent expiry and thus the availability of biosimilars on the market. After one year, rituximab achieved a biosimilar quota of around 57%, based on the proportion of DDD prescribed. With trastuzumab, the proportion was already 67%, also after one year. For bevacizumab, a biosimilar share of around 60% is already set for September, i.e. in the third month after the patent expires. The situation is more differentiated in the different KV regions. Basically, it can be observed: the more established the biosimilars on the market, i.e. the longer it has been since the patent expired, the more leveling occurs between the individual regions. Accordingly, the biosimilar proportions of rituximab currently range between 70% in Mecklenburg-Western Pomerania and 95% in Hamburg. The situation with bevacizumab is completely different. There is a significant gap between the leader Bremen with 83% biosimilar quota and the bottom-placed Saarland with 17%. Even with trastuzumab, the differences are sometimes still considerable (Bremen with 97%, Hamburg with 55%).
For all three substances, there are minimum quotas for the biosimilar proportion of prescribed DDDs at the KV level in regional drug agreements for 2020, agreed between the respective association of statutory health insurance physicians and the statutory health insurance companies. Target quotas for rituximab and trastuzumab have been agreed for 2020 in the following KV regions: Bremen, Lower Saxony, North Rhine, Westphalia-Lippe, Saarland, Hamburg, Saxony and Bavaria. Quotas have already been determined in Bremen, Schleswig-Holstein, Saxony-Anhalt, Saxony and Bavaria for the biosimilar bevacizumab, which has only been available since July. In Thuringia there is also a quota for all monoclonal antibodies. It can therefore be assumed that part of the regionally high biosimilar quotas can also be attributed to the control effect of the KV quotas. For example, in the top 7 regions with the highest proportions of biosimilars for rituximab, there is a minimum quota for the use of biosimilars (source: KV Monitor, INSIGHT Health/Navi4Healthcare).
Contracts: Biosimilars under RV
The obligation to contract also applies to oncological drugs - whether prescribed as finished medicinal products or prescriptions - if a discount agreement exists. Which manufacturers conclude contracts in accordance with Section 130a Paragraph 8 SGB V follows certain patterns, at least for oncological monoclonal antibodies with biosimilar competition. As Figure 2 shows, the discount rates for all three biologics are higher for biosimilars than for the originals. While at
Trastuzumab the proportion of discounted DDD out of all prescribed DDD differs only slightly between the original and biosimilar, the discount rate for rituximab biosimilars is 41.6%, that of the original is 26.5%. The latter, however, is exclusively due to discounted re-imports and parallel imports. The same applies to the trastuzumab original. The original manufacturer had not yet concluded any discount agreements for bevacizumab as of the end of the third quarter of this year. For the biosimilars that have only recently been on the market, however, the discount rate is already 23.6%, although this currently comes from one of the three available biosimilars.
outlook
The oncology market is playing an increasingly important role in total outpatient drug spending; Biologics are a noteworthy group here. With the increasing acceptance among prescribers and, as a result, a continuously increasing market penetration of the available biosimilars, these have now also become widely available in care. This development will continue in the important group of monoclonal antibodies with the impending market entry of further biosimilar competitors, particularly for bevacizumab. It will be exciting to see which discount contract strategies the individual providers will pursue in the future. With the increasing number of competitors, a significantly increasing rate of discounted prescriptions can also be expected. <<

Authors:
Kathrin Pieloth, Esther Zöllner, Christian Luley