- FDA has only approved two biosimilars in 2020.
- No biosimilars have launched in the U.S. since April 2020.
- EMA approves first Novolog® (insulin aspartate), third and fourth Avastin® (bevacizumab), and sixth Herceptin® (trastuzumab) biosimilars.
As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years. Global sales for the top ten branded biologic drugs totaled approximately $81 billion in 2019. In a September 2020 report, the IQVIA Institute for Human Data Science estimated biosimilar sales totaling $80 billion over the next five years compared to $14 billion during the previous five years (2015-2019), and that the availability and use of biosimilar medicines would reduce U.S. drug costs by $100 billion through 2024.
In the FDA’s Center for Drug Evaluation and Research’s (CDER) annual report, the FDA highlighted the ten biosimilar approvals in 2019 under the Biologics Price Competition and Innovation Act (BPCIA) of 2009, which was “designed to create competition, increase patient access, and potentially reduce cost of important therapies.” The FDA’s Biosimilars Action Plan, unveiled in 2018, has been designed to aid the development of a market for biosimilars in order to increase competition for biologic drugs, which make up 40% of U.S. pharmaceutical spending. Competition in the heavily regulated marketplace for these blockbuster therapeutics is expected to substantially impact the pharmaceutical industry and national health systems. To date, the U.S. has considerably lagged behind Europe’s expansion of biosimilar drug options.
Since 2005, the biosimilar regulatory framework in Europe has been implemented through the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA). The CHMP provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by the EMA. Since Sandoz’s somatotropin biosimilar, Omnitrope®, was first authorized on April 12, 2006, an additional 69 applications have been approved in Europe. Seven of the authorizations have been withdrawn post-approval (Table 1).
The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation Act (BPCIA) of 2009. Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States. Sandoz’s filgrastim biosimilar, Zarxio®, received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008. Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991. Subsequent to Zarxio®’s approval, 27 other biosimilar drugs have gained U.S. approval to date (Table 2).
As illustrated in the following graph, while the EU’s significant head start led to an imbalance in the number of biosimilar drugs available in the respective markets, the EU’s relatively higher rate of approvals in recent years has widened its lead over the United States, although the U.S. FDA reversed that trend in 2019 with ten approvals. Through the first nine months of 2020, however, the FDA has only approved two biosimilar products, whereas the EMA has approved eight biosimilar products. The COVID-19 pandemic has likely shifted regulatory and industry focus to vaccines and therapeutics, thereby causing delays in biosimilar approvals.
A recent study of U.S. biosimilar approvals found that most comparative efficacy trials conducted to obtain FDA approval for a biosimilar had a tendency to be larger, longer, and more costly than clinical trials required for originator products. Moreover, the FDA requires animal studies whereas the EMA does not require animal studies to approve a biologic product. Thus, in addition to the patent litigation landscape, there are regulatory hurdles and costs faced by biosimilar applicants that deter or delay biosimilar products from reaching the U.S. market.
Currently, eleven biosimilar applications are under review by the EMA for marketing authorization (Table 3). As an increasing number of patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing. Biosimilars for more than 26 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).
On February 20, 2020, the FDA redefined the term “biological product” to include all “proteins,” which the rule defines as “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” Accordingly, the biosimilar and interchangeable pathways are now open to insulin products in the United States. The EMA already considered insulin a biologic product. This change by the FDA is expected to lead to additional biosimilar approvals because there are already many biosimilar insulin products approved in Europe, and those biosimilar insulin manufacturers will likely seek to expand into the U.S. market. In its press release, the FDA explained that it intends “to balance innovation and competition and facilitate the development and approval of biosimilar and interchangeable products. Getting safe and effective biosimilar and interchangeable products approved will help ensure that the market is competitive, and patients may have more affordable access to the treatments they need.” The FDA approved Mylan’s insulin glargine product SemgleeTM on June 11, 2020, as an equivalent to Sanofi’s Lantus® although it is not considered a biosimilar because approval was under 351(a) of the Public Health Service (PHS) Act (42 U.S.C.. 55. 262(k)). “We are proud to be the first company, following the reference product, to receive FDA approval on and launch both the vial and pen presentations of an insulin glargine treatment with an identical amino acid sequence to Sanofi’s Lantus,” said Mylan CEO Heather Bresch. She estimated the potential market to be more than 30 million Americans. In its press release, Mylan stated that it has submitted all necessary documentation to request FDA approval as a biosimilar to Lantus under the 351(k) pathway and “remains confident in seeking an interchangeability designation.”
Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated October 11, 2020).
Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs.
Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines compiled on September 4, 2020 and published on September 9, 2020).
Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. and biologics that have biosimilars in the regulatory pipeline.
 Based on sales reported by respective manufacturers (1. Humira—Abbvie ($19.17B), 2. Keytruda—Merck ($11.08B), 3. Eylea—Aflibercept ($7.54B), 4. Opdivo—Bristol-Myers-Squibb ($7.20B), 5. Avastin—Roche ($7.12B), 6. Rituxan—Roche ($6.52B), 7. Stelara—Johnson & Johnson ($6.36B), 8. Herceptin—Roche ($6.08B), 9. Enbrel—Pfizer/Amgen ($5.23B), 10. Remicade—Johnson & Johnson/Merck ($4.38B).