Graphic rendering of antibodies in the bloodstream.

Year in Review: Biosimilars

By Laura Karas

Now that 2020 has come to a close, it’s worth taking stock of the progress the United States has made during the last year with respect to biosimilars, pharmaceutical therapies that are highly similar to a reference biologic product and possess no clinically meaningful differences.

Background on Biologics and Biosimilars

Biologic products (or biologics) are complex molecules — typically, but not always, protein based — that are produced in living systems. In contrast to small-molecule drugs like aspirin or penicillin, biologics cannot be reproduced identically due to their complex structures and, in the case of proteins, due to post-translational modifications such as glycosylation, methylation, and acetylation that render each molecule unique. Consequently, there is “batch-to-batch” variability, sometimes referred to as “within-product” variability, in the reference biologic itself. (Manufacturing and testing measures ensure that variation within and across lots does not produce a difference in the biologic product’s safety or efficacy.)

The U.S. Food and Drug Administration (FDA) has labeled biologics “the fastest-growing class” of therapies, encompassing monoclonal antibodies, vaccines, therapeutic serums, toxins, antitoxins, blood and blood components, and proteins like insulin, among other therapies. Biologics tend to be high-priced, making the introduction of lower-priced biosimilars highly anticipated as a means to lower overall drug spending. The Biologics Price Competition and Innovation Act (BPCIA) of 2009, akin to the Hatch-Waxman Act for generic drugs, authorized FDA to create an abbreviated licensure pathway for biosimilars. In March 2015, the country’s first biosimilar, Zarxio (filgrastim-sndz), received approval via this pathway, and a total of twenty-nine biosimilars have been approved to date in the United States.

Biosimilar Launches and Approvals in 2020, and a Thwarted Antitrust Challenge to AbbVie’s Humira

Three new biosimilar products were approved in 2020: Nyvepria (pegfilgrastim-apgf), Hulio (adalimumab-fkjp), and Riabni (rituximab-arrx). It was a relatively slow year for biosimilar approvals as compared to 2019, when a record ten biosimilars gained FDA approval. The pandemic resulted in delays in FDA inspections of manufacturing facilities, which postponed approval of some biologics, including Spectrum’s Rolontis (eflapegrastim), a granulocyte colony-stimulating factor, and Bristol Myers Squibb’s liso-cel (lisocabtagene maraleucel), a CAR-T therapy for treatment of large B-cell lymphoma.

However, 2020 saw a number of launches of previously approved biosimilar products. Pfizer launched Ruxience (rituximab-pvvr) in January 2020 at a 24% discount to the reference biologic Rituxan, and Trazimera (trastuzumab-qyyp) in February at a 22% discount to the reference biologic Herceptin. Teva and Celltrion launched another trastuzumab biosimilar — Herzuma (trastuzumab-pkrb) — in March at a 10% discount to Herceptin’s wholesale acquisition cost, and Merck launched Ontruzant (trastuzumab-dttb) in April at a 15% discount.

Despite twenty-nine biosimilar approvals, marketed biosimilars in the United States lag behind as a result of barriers to market entry, including patents on the reference biologic products. Take, for example, Humira (adalimumab): despite six approved adalimumab biosimilars in the United States, none have reached the market, and market entry is not expected until 2023 (though adalimumab biosimilars entered the European market in October 2018).

In June of 2020, the U.S. District Court for the Northern District of Illinois dismissed a suit against AbbVie alleging that AbbVie’s patent thicket for Humira violated state and federal antitrust laws by blocking competitors from entering the market with adalimumab biosimilars. Calling AbbVie’s practices lawful, Judge Shah of the Illinois district court declined to find that AbbVie’s patent thicket rose to the level of an antitrust violation (“[Plaintiffs] fall short of alleging the kind of competitive harm remedied by antitrust law”), and found protection for the company’s conduct in the Noerr-Pennington doctrine.

Noerr-Pennington shields a party’s petitioning of the government unless the petitions were “objectively baseless.” Here, the judge took the 53.4% success rate of AbbVie’s patent applications at the USPTO (a 0.534 “batting average,” as Judge Shah called it) and a 72.2% success rate in inter partes review as evidence that AbbVie’s patent applications for Humira were “not plausible acts of sham petitioning.” It is worth noting that Judge Shah did find objectively baseless some of AbbVie’s pre-litigation “patent-dance” assertions of Humira patents infringed by would-be competitors, including “nine formulation patents . . . with ingredients that were in neither Sandoz’s biosimilar nor Humira.”

It is true that just over half of AbbVie’s patent applications related to Humira were granted, but just under half were not. So is the glass half full or half empty? If many of the issued Humira patents were of dubious validity, then that likely brings the number of validly issued patents to below 50% of AbbVie’s total applications.

The outcome on appeal is worth watching: plaintiffs submitted an appellant brief to the Seventh Circuit in October, and four amici, including the Federal Trade Commission (FTC), have also submitted briefs. Despite a temporary legal victory for AbbVie, both FTC and FDA continue to monitor drug company tactics with respect to biosimilars, with particular emphasis on detection of false or misleading promotional materials intended to sow confusion about biosimilar safety and efficacy.

Will the U.S. See Its First Interchangeable Biosimilar Approved in 2021?

The United States has yet to see an interchangeable biosimilar product receive FDA approval.

According to statutory standards, interchangeable products must be shown to produce “the same clinical result as the reference product in any given patient” and must be shown safe and efficacious when switching between the reference biologic and the interchangeable biosimilar. In previous guidance documents, FDA provided more explicit instruction for industry on the data required to support approval as an interchangeable product.

Recall from earlier in this post that “within-product” variability exists within and across lots of the reference biologic itself. Concerns regarding immune reactions as a result of switching between a biosimilar and a reference biologic may be unfounded, because, as some researchers have noted, “[the risk of immunogenicity] is unlikely to be greater than the risk of switching between two different batches of a biological.”

Interchangeability has the potential to increase the usage of biosimilars considerably by opening the door to pharmacy-level substitution, a key state policy that has facilitated generic drug utilization in the U.S.

According to the BPCIA’s definition of interchangeability (§ 351(i)(3)), a biosimilar product licensed as interchangeable may be substituted for its reference biologic without a provider’s express approval, a practice not currently permitted for non-interchangeable biosimilars. Yet states retain authority over pharmacy-level substitution policies. Patient and prescriber involvement — for example, through provision of notice of the substitution — remain important considerations, and most European countries still require provider involvement to switch a patient to a biosimilar.

In November 2020, FDA released its most recent draft guidance for industry on biosimilarity and interchangeability. The draft guidance touched on the issue of FDA labeling of interchangeable products, and specified that these products should bear annotation alerting providers to an interchangeable product’s features. The release of this guidance may foreshadow the approval of the first interchangeable biosimilar product this year.

Laura Karas

Dr. Laura Karas is a student at Harvard Law School and a Petrie-Flom Student Fellow for the 2020-21 academic year.

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