Updated November 15, 2021

  • FDA and EMA both approve first biosimilar version of Lucentis® (ranbizumab).
  • FDA has approved only two biosimilars in 2021 after only approving three in 2020.
  • EMA approves four more Avastin® (bevacizumab) biosimilars, bringing the total number of approved bevacizumab approvals to nine, but also withdraws approval of two of bevacizumab and one rituximab biosimilars.
  • Given the increasing number of approved biosimilars in Europe, biosimilar manufacturers are increasingly deciding to not market their products due to commercial reasons.

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 $85 billion in 2020[1].  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 three biosimilar approvals in 2020 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 81 applications have been approved in Europe.  Fourteen of the authorizations have been withdrawn post-approval (Table 1).  Most recently, market authorization holders for Equidacent® (bevacizumab), Lextemy (bevacizumab), and Ritemvia® (rituximab) requested that their marketing authorizations be withdrawn due to commercial reasons.  There are seven other approved bevacizumab biosimilars and five other approved rituximab biosimilars.

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, 30 other biosimilar drugs have gained U.S. approval to date including two interchangeable products (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 2021, however, the FDA has only approved two biosimilar products, whereas the EMA has approved eight biosimilar products.  However, given the increasing competition between biosimilar manufacturers in Europe, four EMA-authorized biosimilar products have been withdrawn in 2021.

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.  Further, given the difficult patent litigation and competitive landscapes, there appear to be fewer biosimilar BLAs than in 2017-2019, and launches of FDA-approved adalimumab and rituximab biosimilars are delayed due to settlements of patent litigations.  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, sixteen 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 28 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).

On September 17, 2021, the FDA approved Samsung Bioepis and Biogen’s ranibizumab ByoovizTM as the first biosimilar to Lucentis® for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), and myopic choroidal neovascularization (mCNV).  “In the United States, approximately 11 million people are affected with AMD and the prevalence of advanced AMD is growing due to the aging population. The approval of the first ranibizumab biosimilar in the U.S. is a monumental milestone for people living with retinal vascular disorders in the U.S.,” said Kyung-Ah Kim, Senior Vice President and Development Division Leader, at Samsung Bioepis. “The approval of BYOOVIZ™ underscores our continued commitment to providing valuable treatment options for people who do not have access to life-enhancing biologic medicines around the world,” she added.  “We are very excited to be able to open a new chapter with the approval of BYOOVIZ™ in the U.S. This approval represents a great step toward the advancement of a new therapeutic option addressing debilitating disease progression of patients with retinal vascular disorders in the U.S.,” said Ian Henshaw, Senior Vice President and Global Head of Biosimilars at Biogen. “Biosimilars could help broaden patient access to more affordable treatments and generate healthcare savings to offset rising costs of these complex diseases while ensuring sustainability of healthcare systems.”  EMA also approved ByoovizTM in August 2021 as the first ranibizumab biosimilar in Europe.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated November 15, 2021).

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 November 3, 2021 and published on November 8, 2021). 

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. and biologics that have biosimilars in the regulatory pipeline.

[1] Based on sales reported by respective manufacturers (1. Humira—Abbvie ($20.39B), 2. Keytruda—Merck ($14.38B), 3. Eylea—Aflibercept ($8.36B), 4. Stelara—Johnson & Johnson ($7.94B), 5. Opdivo—Bristol-Myers-Squibb ($7.92B), 6. Enbrel—Pfizer/Amgen ($6.37B), 7. Avastin—Roche ($5.32B), 8. Trulicity—Eli Lilly ($5.07B), 9. Ocrevus—Roche ($4.61B), 10. Rituxan—Roche ($4.52B).