US Biosimilar Regulatory Roundup: 2019

When it comes to US biosimilars, 2019 was the busiest year yet for regulatory activity, with a bevy of new approvals and the publication of long-awaited guidance documents.

The FDA began the year with the approval of Samsung Bioepis’ Ontruzant, which gained authorization in January; the product, a trastuzumab biosimilar referencing Herceptin, was the third biosimilar trastuzumab to be approved by the FDA. Following in March, the FDA approved Pfizer’s trastuzumab biosimilar, Trazimera. The ranks of trastuzumab biosimilars grew again in June, with the approval of Amgen’s Kanjinti, which launched in July.

In April, the FDA approved the second etanercept biosimilar, referencing Enbrel, in the United States: Samsung Bioepis’ Eticovo, which joined Sandoz’s Erelzi as approved, but not yet launched, etanercept competitors.

In June, the FDA approved its second bevacizumab biosimilar, Pfizer’s Zirabev, which will eventually compete with both the reference Avastin and Amgen’s approved and launched biosimilar, Mvasi. Pfizer next saw its rituximab biosimilar, Ruxience, referencing Rituxan, approved in July .

Samsung Bioepis joined the growing number of biosimilar developers with approved but unlaunched adalimumab biosimilars in July when the FDA approved its Hadlima. No biosimilars are expected to launch before 2023, after biosimilar developers struck deals with Humira-maker AbbVie to end patent litigation. Pfizer’s Abrilada, another biosimilar adalimumab, also gained FDA approval in November.

Also in November, Sandoz gained approval for Ziextenzo, the third biosimilar pegfilgrastim, referencing Neulasta, to gain regulatory clearance in the United States. The biosimilar launched shortly thereafter, making pegfilgrastim the first product to have 3 competing biosimilars commercially available in the United States.

Finally, in December, the FDA approved a fourth infliximab biosimilar referencing Remicade: Amgen’s Avsola. The drug will compete with fellow biosimilars Inflectra and Renflexis, although it is unlikely to compete with Ixifi, which sponsor Pfizer has indicated will not enter the US market.

Drug maker Tanvex did not get to count itself among the makers of an FDA-approved biosimilar filgrastim, however; in October, the agency issued a Complete Response Letter (CRL) for TX01, a proposed biosimilar to Neupogen.

Also facing regulatory setbacks were Mylan and partner Biocon, which in September received a second CRL for their proposed follow-on insulin glargine, referencing Lantus.

In terms of guidance documents, in May, the FDA release its long-awaited final guidance on demonstrating interchangeability of a biosimilar with its reference. Among the features of the guidance is a description of dedicated switching studies that will be used to demonstrate interchangeability with the reference product.

However, in November, the FDA made waves in the biosimilars world when it released draft guidance on insulin biosimilars ahead of the March 2020 transition of these products to regulation as biologics. That guidance indicated that, for interchangeable insulins, switching studies will not generally be necessary. Also related to insulins was a proposed rule, issued in June, to amend regulations concerning the use of master files for the transitioning biologics.

Also in May, the agency published draft guidance on the design and evaluation of comparative analytical studies that are intended to support a demonstration of biosimilarity. That guidance came after a previous draft guidance was withdrawn in 2018. Numerous parties have asked the FDA for further clarification of some key issues within the guidance, including how to assign potency of reference standards that show lot-to-lot variation.

This year, the FDA also released a suite of resources to educate patients about biosimilars. The new materials, “Biosimilars Basics for Patients,” explain that biosimilars are safe and effective medications. The FDA describes biosimilars are being made “from natural sources” and developed “using advanced science.”

Among the more controversial guidance documents published by the FDA in 2019 was a March guidance in which the FDA said it no longer intends to retroactively give approved biologics 4-letter suffixes devoid of meaning, but that it will assign these suffixes to newly approved biologic products. The then commissioner of the FDA, Scott Gottlieb, MD, said that retroactively assigning suffixes to biologics would be costly, and he argued that those costs could be passed to patients. Other regulatory territories, such as Europe and Canada, have expressly opted for suffix-free naming conventions.

Finally, regulators from the United States, along with those from Australia, Brazil, Canada, and China, as well as the European Union and elsewhere, issued a statement voicing confidence in biosimilars. The International Coalition of Medicines Regulatory Authorities said in August that biosimilars have been used safely for many years, and no relevant differences in adverse effects have been observed between biosimilars and their references.

As for what’s ahead in 2020 and beyond, some stakeholders are hoping to see the FDA revisit its current “totality of the evidence” approach to demonstrating biosimilarity supplanted by a different paradigm. In August, a paper in BioDrugs proposed a “confirmation of sufficient likeness” approach that would not routinely require bridging studies, nonclinical in vivo studies, human pharmacodynamic studies (with potential exceptions for insulins), or powered human efficacy studies.

Instead, it would rely on comprehensive analytical studies, nonclinical in vitro functional tests, human pharmacokinetic studies, and human immunogenicity studies, including transitions.