Trastuzumab’s Evergreening Impact on Biosimilars, Health Care Costs

The introduction of trastuzumab biosimilars in the Netherlands led to significant price reductions and increased market share, despite the evergreening strategy implemented by the pharmaceutical company, according to a study published in The European Journal of Health Economics.1

Major concerns exist regarding the expensive costs of medicines that apply pressure on total health care expenditures, a result of monopoly prices set by pharmaceutical companies since the drugs they manufacture are protected by patents. Original patents are usually valid for 20 years and can extend for an additional 5 years if the development process is lengthier and market authorization is successful.

The "patent dance" is a US legal process designed to streamline patent disputes between biosimilar manufacturers and reference product sponsors.2 It involves exchanging information on patents and their potential infringement, aiming to minimize future legal costs.

Pharmaceutical companies often use "evergreening" to extend drug exclusivity by filing new patents on slightly modified versions.1 This can delay the entry of biosimilars like trastuzumab, potentially leading to societal losses. Assessing the impact of evergreening on biosimilar uptake is crucial.

The study authors set out to explore “the dynamic market share and public health care costs of trastuzumab’s evergreening (subcutaneous) variant during introduction of trastuzumab’s competitive biosimilar variant in the Netherlands.”

Trastuzumab (Herceptin) was approved for the European market by Roche in August 2000 to treat patients with early-stage and metastatic breast cancers. The drug entered the market as an intravenously administered medication that drastically improves survival outcomes for patients with HER2-overexpressing breast cancer.

Trastuzumab is also one of the first biological drugs where the patent expired and an evergreening strategy was applied. The patent for the intravenous trastuzumab expired in 2014, allowing biosimilars to enter the market.

The patent for the subcutaneous administration form remains valid until 2030, limiting the current availability of biosimilars to intravenous trastuzumab.

The study utilized proprietary insurance claim data of all patients who were treated with trastuzumab in Dutch hospitals between January 2013 and December 2020. The average number of treatments per month is 3519.95 with 580.61 average treatments per hospital per year and 4628.97 for all years. About 410.48 mg of trastuzumab and 451.99 mg of the biosimilar were administered per intravenous treatment. The subcutaneous trastuzumab originator has a fixed dosage of 600 mg.

Almost all the participants were women (99.67%) with an average of 56.78 years old. Treatments were given across 73 hospitals in the Netherlands, including 8 academic hospitals, 25 top clinical hospitals, and 40 general hospitals.

The average treatment cycle of a patient consisted of 4.80 treatments of trastuzumab given in combination with chemotherapy whereas 13.16 treatments were given without chemotherapy. There was 33.13% of all intravenous-administered trastuzumab treatments (originator and biosimilars) given in combination with chemotherapy.

An upward trend was identified in the total amount of trastuzumab treatments from January 2013 until January 2014 but then decreases slightly, remaining steady at 3500 treatments per month until June 2018. Following the introduction of biosimilars in 2018, the total use increases until a peak in January 2019. A significant drop in trastuzumab treatments around April 2020 could be attributed to the COVID-19 pandemic.

When the subcutaneous trastuzumab originator was introduced in 2014, it led to a decrease in the use of the intravenous originator and an increase in subcutaneous originators up to a point in 2017 with a 50% to 50% distribution. There was a steep decline in intravenous trastuzumab originator after 2018 when the biosimilars were introduced but it is barely used a few months later. By 2020, biosimilars are used for an estimated 80% of the treatments and subcutaneous trastuzumab originator for 20%.

Hospitals displayed different uptake patterns of both subcutaneous trastuzumab following the introduction in 2014 and biosimilars in 2018. One hospital kept administering subcutaneous trastuzumab for all treatments while others switched using biosimilars for 90% of the treatments. Some hospitals decided not to switch to subcutaneous trastuzumab but replaced intravenous trastuzumab for biosimilars shortly after the introduction. Hospitals also differed in speed in which they switched to subcutaneous trastuzumab and biosimilars.

The study found the introduction of subcutaneous administration form did not change the price level of trastuzumab, whereas the introduction of biosimilars was accompanied by lowering price effects associated with biosimilars. The study also found an increased volume effect after biosimilar introduction, switching decisions made on the hospital level and influenced by patient volume, and health insurer specific effects in the use of subcutaneous trastuzumab.

The financial impact of the evergreening strategy is difficult to determine, potentially limiting study results, and should be interpreted with caution. Additionally, claims data was unable to differentiate between actual costs of administering intravenously or subcutaneously.

Future research is necessary on the impact of pharmaceutical strategies nearing patent expiration on the uptake of biosimilars and the public health care costs. A higher uptake for trastuzumab was recognized in the Dutch market that led to more competitive market structure and significant price drops.

“We recommend a more explicit societal debate to consider if the potential benefits of subcutaneous trastuzumab are worth the additional costs, and at which price it should be reimbursed as the part of the benefit package,” study authors concluded.

References

1. Kirshner G, Makai P, Brouns C, Timmers L, Kemp R. The impact of an 'evergreening' strategy nearing patent expiration on the uptake of biosimilars and public healthcare costs: a case study on the introduction of a second administration form of trastuzumab in The Netherlands. Eur J Health Econ. 2024;25(7):1147-1163. doi:10.1007/s10198-023-01648-w

2. Jeremias S. Breaking down biosimilar barriers: the patent system. The Center for Biosimilars®. November 11, 2024. Accessed December 12, 2024. https://www.centerforbiosimilars.com/view/breaking-down-biosimilar-barriers-the-patent-system