As of July 22, the FDA has approved 57 biosimilars for 17 reference biologics. It has been a decade since Sandoz filed its 351(k) application to become the first biosimilar marketed in the US. It seems like ages ago.
Filed for approval on May 8, 2024, Zarxio® (filgrastim-sndz) was approved by the FDA on March 6, 2015. Today, the European Medicines Agency (EMA) has approved over 100 biosimilars, roughly doubling the US count. However, the trajectories are not very different, and considering the reference drug categories subject to biosimilar approval, it may not be as wide a gap as you might think. Let’s do a ten-year anniversary comparison of our own.
The first biosimilar approved for the European market was also a Sandoz product, Omnitrope® (somatropin) on April 12, 2006. (Note that the EMA does not assign four-letter suffixes to its biosimilar products.) Based on data from the Generics and Biosimilars Initiative (GaBI), the EMA has approved 106 biosimilars for 23 different reference drugs (see the Table below) as of July 22, 2024. According to GaBI, they are from the following major pharmaceutical classes: erythropoiesis-stimulating agents, follicle-stimulating hormone, granulocyte colony–stimulating factors, human growth hormone, insulin, monoclonal antibodies, parathyroid hormone, TNF inhibitor, and vascular endothelial growth factor inhibitors. In the US, several of these classes (i.e., human growth hormone, follicle-stimulating hormone, parathyroid hormone, and insulin) were only transitioned to biosimilar status; that is, existing agents were considered innovator biologics but after March 2020, new drug applications would be under the biosimilar regulatory pathway. Except for insulin, none of the other drug hormone categories approved as biosimilars by the EMA and not by the FDA are likely to see much biosimilar competition in the US. Several, such as the growth hormone and follicle-stimulating hormone, have been approved as biologics prior to the transition date. Enoxaparin is subject to generic competition in the US. Also, the US does not have an epoetin-beta or -zeta molecule.
Our assessment after 5 years of biosimilar experience in the US reflects today’s reality: Despite a delayed start in 2014, the rate of FDA approvals has accelerated. By August 2019, the FDA had approved 23 biosimilars, and that performance is not too dissimilar from that for the EMA in its first 5 years of biosimilar approvals (2006–2010). By the EMA’s 10-year biosimilar regulatory anniversary (April 2016), the number of approvals was only in the low 20s, This predated their receipt of the deluge of oncology and autoimmune biosimilar applications, so it is a flawed comparison that is unduly affected by the timing of expiring patents and exclusivities.
Of course, the number of products approved and the number of products launched/still marketed are very different. Some 17 biosimilars in Europe were withdrawn by their manufacturers after receiving approval, leaving 89 biosimilars approved by the EMA. In the US, this has been limited to a couple of cases so far: (Pfizer’s Ixifi®, an infliximab that it decided not to market, avoiding competition with Inflectra®, and a recent example of an adalimumab biosimilar being sold and whose continued marketing is not assured).
| Biosimilar Approvals by Reference Product in the US vs. EU | ||
| Reference Product | Approved by FDA | Approved by EMA |
| Adalimumab | ● | ● |
| Aflibercept | ● | ● |
| Bevacizumab | ● | ● |
| Denosumab | ● | ● |
| Eculizumab | ● | ● |
| Enoxaparin sodium | ● | |
| Epoetin-alfa | ● | ● |
| Epoetin-zeta | ● | |
| Etanercept | ● | ● |
| Filgrastim | ● | ● |
| Follitropin-alfa | ● | |
| Infliximab | ● | ● |
| Insulin aspart | ● | |
| Insulin glargine | ● | ● |
| Insulin lispro | ● | |
| Natalizumab | ● | ● |
| Omalizumab | ● | |
| Pegfilgrastim | ● | ● |
| Ranibizumab | ● | ● |
| Rituximab | ● | ● |
| Somatropin | ● | |
| Teriparatide | ● | |
| Tocilizumab | ● | ● |
| Trastuzumab | ● | ● |
| Ustekinumab | ● | ● |
Experience has taught us that the patent system in the EU results generally in earlier biosimilar launches. The patent mazes associated with US reference biologics have no doubt delayed several biosimilar manufacturers from completing trials and submitting 351(k) applications to the FDA. Patent mazes have famously delayed launch of adalimumab and etanercept biosimilars, but it is unclear at this point whether any other biosimilar manufacturers would have entered the competition for these biologics. With adalimumab, an 11th or 12th manufacturer would be hard to fathom. Outside of adalimumab and etanercept, however, the launch of a US biosimilar to a second- or third-generation biosimilar has been within about 1 year of the EU launch. It seems that the die has been cast, with patent settlement agreements seemingly limiting a longer wait for litigation to be completed.
On the whole, the FDA’s record of granting biosimilar marketing authorization has mirrored that of the EMA’s, considering the age of the respective biosimilar approval programs. If legislators or regulators in the US can narrow the guardrails on enforceable patents, this gap should narrow with the next large crop of biologic targets.
