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Legal Obstacles to Biosimilar Market Entry

By Laura Karas, MD, MPH; Rachel Sachs, JD, MPH; Gerard Anderson, PhD

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Citation

Karas L, Sachs R, Anderson G. Legal obstacles to biosimilar market entry. HPHR. 2021;28. 

Legal Obstacles to Biosimilar Market Entry

Abstract

Improving the market availability and penetration of biosimilars, “follow-on” versions of biologic products, will require attention to key legal obstacles. Because biosimilars offer the potential for sizeable cost savings to payors and improved access to biologic drugs for patients, obstacles to the timely licensure and market availability of biosimilars are of major public health significance. Issues around intellectual property, potentially anticompetitive contractual arrangements with purchasers and insurers, and laws governing automatic substitution of biosimilars for biologics merit particular attention. This Article examines several key legal obstacles to biosimilar market entry in the United States, including (1) the complexity and imprecise boundaries of the exchange of patent information codified in the BPCIA; (2) patent thickets that protect biologic reference products; (3) unsettled antitrust law surrounding reverse payment patent settlements (i.e., “pay-for-delay” agreements); (4) contractual arrangements such as bundled purchase agreements and formulary exclusivity provisions; and (5) state laws that regulate substitution of biosimilars for biologics at the pharmacy level.  Strategies to address these obstacles include reforms to the patent system to curb issuance of ancillary secondary patents intended to delay competition, greater transparency around biologic patents, reconsideration of the need for a regulatory designation of interchangeability, and better detection and enforcement of deliberately anticompetitive practices.

Introduction

 

Biologic drugs arguably pose one of the most formidable contemporary challenges to reining in pharmaceutical drug spending. The reasons for this are multifold: Biologic drugs constitute a rapidly growing class of drugs that tend to be high priced. And, at present, they are less likely than innovator small-molecule drugs to face competition from a biosimilar (or, in the case of small-molecule drugs, a generic). Often physician administered by injection or infusion in a doctor’s office or hospital, biologic drugs and their biosimilar counterparts are commonly, though not exclusively, covered under Medicare Part B.[1] Biologics have been the primary drivers of Medicare Part B drug spending growth, accounting for 92% of Part B drug spending growth from 2006 to 2017[2] and constituting 77% of Part B drug spending in 2017 alone.2 High biologic prices and price increases, in addition to newly licensed biologics and increases in utilization of existing biologics, contribute to spending growth; a recent study found that more than half of spending increases for biologic disease-modifying antirheumatic drugs covered under Medicare Part D could be accounted for by unit price increases for these drugs.[3] Although to date biosimilars have offered only a modest price reduction relative to their reference products, the more frequently lower-priced biosimilars enter the marketplace, the greater the cost savings that can be achieved. For this reason, increasing attention has been paid to licensure of biosimilars in the United States and to their entry into the market to compete for sales with their respective reference biologic products.

 

A biosimilar is defined by statute as “highly similar” to the reference biologic and expected to produce the same clinical outcome,[4] but otherwise equivalent in dose, strength, route of administration, and mechanism of action.[5] The U.S. Food and Drug Administration (FDA) licensed the first biosimilar in 2015, five years after the enactment of the Biologics Price Competition and Innovation Act (BPCIA), the U.S. law establishing an abbreviated approval pathway for biosimilars. As of August 1, 2021, the FDA has licensed 30 biosimilars,[6] two-thirds of which have reached the market, whereas 65 biosimilars currently have marketing authorization in the European Union.[7] Only three biosimilars were licensed by the FDA during the 2020 calendar year, whereas five, seven, and ten biosimilars were licensed in 2017, 2018, and 2019, respectively. Table 1 lists all biosimilars licensed by the FDA as of August 1, 2021; their corresponding reference products; manufacturer; date of FDA licensure; and whether the product is on the market in the United States. Although this article does not undertake a cross-regional comparison, regulatory differences likely play a major role in the marked disparity in approved biosimilars and biosimilar adoption between the United States and the European Union,[8] as do post-market factors such as formulary placement, provider familiarity and comfort with prescribing biosimilars, and biosimilar product nomenclature.[9],[10],[11],[12].

 

This Article contends that legal and regulatory factors stand as critical obstacles to biosimilar market entry in the United States. Five legal impediments to U.S. market entry of biosimilars warrant particular attention: (1) the complexity and imprecise boundaries of the exchange of patent information codified in the BPCIA; (2) patent thickets that protect biologic reference products; (3) unsettled antitrust law surrounding reverse payment patent settlements (i.e., “pay-for-delay” agreements); (4) contractual arrangements such as bundled purchase agreements and formulary exclusivity provisions; and (5) state laws that regulate substitution of biosimilars for biologics at the pharmacy level. This article concludes by discussing reforms that can accelerate the market entry of biosimilars in the United States.

 

Litigation of the “Patent Dance”

The BPCIA lays out a series of exchanges of patent information colloquially termed the “patent dance” between the biosimilar manufacturer (the abbreviated Biologics License Application, or aBLA, applicant) and the biologic manufacturer (termed the reference product sponsor).[13] Legislators intended the BPCIA’s exchange of patent information to create a “simple, streamlined patent resolution process” in order to “ensure that litigation surrounding relevant patents will be resolved expeditiously and prior to the launch of the biosimilar product.”[14]

 

Although designed to facilitate a timely resolution to patent challenges by stipulating a succession of pre-litigation exchanges, the patent dance has instead become a source of delay. The first biosimilar licensed in the United States, filgrastim-sndz, was the subject of litigation between aBLA applicant Sandoz and reference product sponsor Amgen over legal remedies for Sandoz’s failure to comply with the BPCIA’s patent dance. In 2017, the Supreme Court held in Sandoz Inc. v. Amgen Inc. that a biosimilar manufacturer could not be compelled by federal court injunction to share its aBLA application and manufacturing information as laid out in the BPCIA under 42 U.S.C. § 262(l)(2)(A).[15] Although the Court declined to rule definitively on whether the BPCIA’s exchange of information is mandatory or conditional, this decision has, in effect, made the initiation of the patent dance optional for biosimilar applicants under federal law. It does not mean, however, that the BPCIA fails to provide a means for judicial resolution of patent disputes; upon the aBLA applicant’s failure to share application and manufacturing information, the reference product sponsor can initiate a patent infringement suit against the aBLA applicant under 42 U.S.C. § 262(l)(9)(C). Following in the footsteps of Sandoz, some aBLA applicants have refused to participate in various aspects of the patent dance. This has prompted additional federal suits that have tested the boundaries of what the reference product sponsor must do to compel disclosure. [16][17]

 

The BPCIA also requires the aBLA applicant to notify the reference product sponsor not later than 180 days prior to the commercial marketing of the biosimilar.[18] The Supreme Court in Sandoz v. Amgen clarified the timing of this notice: the aBLA applicant may provide its 180-day notice to the reference product sponsor before or after the FDA has licensed the biosimilar.[19] This ruling effectively permits a biosimilar manufacturer to provide its notice of commercial marketing in advance of FDA licensure, thereby avoiding a de facto six-month extension of the reference product sponsor’s market exclusivity during the 180-day notification period. (Under the BPCIA, all biologic drugs receive 12 years of market exclusivity from the date of licensure of the reference product, during which time no biosimilar can be licensed.[20])

 

While Sandoz v. Amgen was a decision favorable to makers of biosimilars, subsequent decisions have been mixed. For example, on appeal before the Federal Circuit, Amgen Inc. v. Hospira, Inc. was decided on grounds favorable to reference product sponsor Amgen. The Federal Circuit declined to overturn the lower court’s finding of patent infringement by Hospira’s erythropoietin biosimilar and found inapplicable a statutory safe harbor defense for certain batches of erythropoietin that Hospira manufactured using a patent-protected method; the Federal Circuit rejected Hospira’s argument that these batches were used solely for testing required for FDA approval of its biosimilar.[21]

 

The patent dance has fostered gamesmanship, spawned litigation, and produced inefficiency in the resolution of patent disputes between reference product sponsors and aBLA applicants, precisely the opposite of a “simple, streamlined . . . process”14 or “carefully calibrated scheme,” as the Supreme Court in the unanimous decision of Sandoz v. Amgen described it.[22]

 

Patent Thickets and Secondary Patenting

The patent dance is made that much more complex as a result of the large number of patents on biologics, sometimes exceeding one hundred per drug.[23] In addition to seeking a patent on the active pharmaceutical ingredient, drug makers often seek a number of secondary patents for a given drug, whether small molecule or biologic. These later-issued secondary patents typically protect peripheral features of the drug product such as a new route of administration, a new but minor variation of the original drug’s molecular structure, a new method of use, or a sustained-release feature.[24],[25], [26] Secondary patents can impose prohibitive costs on potential market entrants who seek to understand the legitimate scope of patent protection for an approved small-molecule drug or biologic. A “patent thicket” refers to “a dense web of overlapping intellectual property rights,”[27] composed of numerous secondary patents in the case of pharmaceutical drugs, that functions as a deterrent to competitors seeking to commercialize a product without infringement.

 

Concerns exist that many secondary patents protect claims that are minor variations of previous patents and are therefore not worthy of the same degree of patent protection as are patents on the underlying compound.24-26 Strategic use of patents to ward off competitors and extend the period of monopoly drug pricing falls within the ambit of “evergreening,” or pharmaceutical drug “life-cycle management.”[28] Patent thickets and secondary patenting tend to be less problematic for small-molecule drugs than for biologics, in part because small-molecule drugs warrant fewer patents as a result of their less complex chemical structures and simpler manufacturing methods, and in part because the FDA’s Orange Book affords greater visibility into small-molecule drug patents. (FDA’s Orange Book is an electronic repository of patent information, exclusivities, and therapeutic equivalents of FDA-approved drug products; biologics, however, are not included.)

 

Empirical studies of small-molecule drugs have demonstrated that secondary patents can extend the total period of patent protection by several years to more than a decade in some cases.24-26 Vast differences can also exist in the size of patent thickets across jurisdictions. For instance, one report found that 247 patent applications have been filed in the United States for adalimumab (Humira), whereas just 76 patent applications on adalimumab have been filed in Europe.[29] Humira is somewhat exceptional, given that it is the top-selling drug worldwide[30] and so greater incentives exist for AbbVie, the maker of Humira, to maximize intellectual property protections for the drug, but it is nonetheless a fair representative of biologics with respect to the numerosity of patents.

 

Intellectual property protections have been central to delays in the market entry of licensed biosimilars in the United States. For example, the primary patent for Humira expired in 2016,[31] but six adalimumab biosimilars will not reach the U.S. market until 2023,[32] seven years after expiry of the primary patent and more than twenty years after adalimumab was first approved by the FDA in 2002. The delay is due to settlement agreements between brand manufacturer AbbVie and biosimilar manufacturers over unexpired secondary patents on Humira in the United States.[33] To provide another example, the primary patent on etanercept (Enbrel) expired in 2010; however, at least 57 patent applications have been filed for Enbrel in the United States and at least 19 patents are issued or pending.[34] Two biosimilars to etanercept — Sandoz’s etanercept-szzs (Erelzi) and Samsung Bioepis’ etanercept-ykro (Eticovo) — have not launched in the United States due to patent litigation with Enbrel’s manufacturer, Amgen.[35]

 

In July 2020, the Federal Circuit in Immunex Corp. v. Sandoz Inc. upheld a finding of validity for Enbrel patents against a challenge by biosimilar manufacturer Sandoz.[36] The outcome of the litigation may delay entry of etanercept biosimilars until 2029, more than thirty years after Enbrel was FDA approved in 1998.[37] Importantly, the Federal Circuit declined to find two key Enbrel patents invalid for reasons of obviousness-type double patenting,[38] a judicially created doctrine that prevents the patenting of claims that are obvious variants of claims made in earlier, commonly owned patents. The policy motivation behind the doctrine is to avoid unjustified patent term extensions from issuance of patents to the same owner that are not sufficiently distinct. Roche had licensed Enbrel patents to Immunex, which obtained FDA approval of Enbrel in 1998; Immunex was later acquired by Amgen, the current maker of Enbrel. In the suit, Sandoz challenged the validity of Enbrel patents to which Immunex had an exclusive license. Ultimately, the Federal Circuit found obviousness-type double patenting inapplicable because all substantial rights to the patents in question were not transferred from Roche to Immunex,38 thus defeating a finding that the patents in question were commonly owned by Immunex, a necessary precondition for obviousness-type double patenting. Licensing of intellectual property and questions regarding ownership of patents in light of acquisition and licensure are fairly common for pharmaceutical patents. Whether this holding portends difficulty for defenses of obviousness-type double patenting in biologic patent infringement suits, especially those involving licensees, remains to be seen.

 

Reverse Payment Patent Settlements (“Pay-for-Delay”)

“Pay-for-delay” deals are settlement agreements in patent infringement lawsuits in which a brand pharmaceutical company typically makes a large payment to a generic company in exchange for a delay in generic entry. These deals cost consumers billions of dollars annually due to agreed-upon delays in bringing more affordable generic drugs to market.[39] The Federal Trade Commission (FTC) and Department of Justice (DOJ) monitor pharmaceutical patent settlements for pay-for-delay activity pursuant to the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA). The 2018 Patient Right to Know Drug Prices Act amended the MMA to expand mandatory reporting of settlement agreements to encompass those agreements between makers of biologics and biosimilars.[40]

 

It remains to be seen whether the FTC and DOJ will use these mandatory reporting laws to effectively detect and penalize pay-for-delay deals between biologic and biosimilar manufacturers. In 2013, the Supreme Court ruled in FTC v. Actavis, Inc. that pay-for-delay settlements between a brand and generic company may have anticompetitive effects on the market and may violate federal antitrust laws, but are not presumed to do so.[41] The deals between brand and follow-on firms have now evolved far beyond simple payments and often include agreements to provide other items of value, such as a promise not to launch an authorized generic or a deal to segment markets.[42, [43] It is more difficult for courts to determine whether these types of agreements violate antitrust laws.[44] Whether the various Humira-related settlement agreements described in the previous section, which delay market entry of already licensed adalimumab biosimilars in the United States, could qualify as unlawful pay-for-delay arrangements remains an unsettled question. A district court has dismissed claims that AbbVie’s deals with biosimilar manufacturers delaying U.S. market entry of Humira biosimilars until 2023 while allowing earlier European market entry constitute unlawful reverse payments.[45] The case, however, is on appeal before the Seventh Circuit,[46] and it may eventually reach the Supreme Court, at which point the Court will have an opportunity to clarify the law surrounding pay-for-delay deals post-Actavis. Although Solvay’s Androgel, the drug at issue in Actavis, was a small-molecule drug, biologics may in fact provide a greater incentive for drug companies to engage in pay-for-delay settlements due to the sheer number of patents potentially subject to dispute and the higher financial stakes associated with biologics.

 

Contractual Arrangements: Bundled Rebates and Formulary Exclusivity

Similar to manufacturers of small-molecule drugs, manufacturers of biologics commonly offer rebates to purchasers and insurers. Recent lawsuits have charged biologic manufacturers with unlawfully employing rebates to maintain market share and squelch competition in the face of biosimilar market entry. Pfizer filed suit against Johnson & Johnson in 2017 alleging that Johnson & Johnson used rebates on “bundles” of drugs within its product line and exclusionary contract terms with insurers to obtain preferred formulary placement for its biologic drug infliximab (Remicade), to the detriment of Pfizer’s nascent biosimilar infliximab-dyyb (Inflectra).[47] Pfizer alleged in the complaint that Inflectra’s share of the market remained below 4% one year after launch due to Johnson & Johnson’s exclusionary tactics,[48] which it claimed run afoul of antitrust laws. Johnson & Johnson denied any plausible antitrust injury, defending its use of multiproduct bundled rebates and arguing that Pfizer failed to demonstrate its own efforts to compete by offering its own bundled rebate, for example, or by lowering the price of Inflectra.[49]

 

Since 2017, market share growth for infliximab biosimilars has remained sluggish, and by some reports biosimilars now capture only one-fifth of the market for infliximab.[50] In August 2018, a U.S. district court for the Eastern District of Pennsylvania denied a motion to dismiss Pfizer’s suit against Johnson & Johnson,[51] but in July of this year, Pfizer and Johnson & Johnson settled out of court.[52] Settlement was likely a strategic decision on the part of Johnson & Johnson to avoid public scrutiny of its business practices that would have accompanied a trial, especially at a time when the new presidential administration has signaled that biosimilar competition will be a top priority.[53] Remicade-related lawsuits brought by the pharmacy chain Walgreen Co. and others continue.52

 

While bundling is common across industries and not necessarily anticompetitive, it may unlawfully foreclose competition under certain circumstances,[54] such as when a product in a competitive market is linked to a product in a noncompetitive one.[55] Faced with rebates on multiproduct bundles and the threat of no rebates otherwise, purchasers and insurers may have little choice but to concede to the terms of the brand company. Patients suffer economic injury in the form of higher out-of-pocket costs when a more expensive biologic drug receives preferred or exclusive formulary status as a result of bundled rebates or other forms of exclusive dealing.

Bundled rebates may present a more acute challenge to biosimilars than to small-molecule drugs because of high list prices for biologics and the lack of interchangeable status for most biosimilars in the United States. Often, lack of interchangeability has the practical effect of limiting a biosimilar’s market penetration to only a subset of the reference biologic’s market: new patients and those who fail or cannot tolerate therapy with the reference biologic. Consequently, a bundled rebate involving a biologic is more valuable to an insurer or purchaser (due to higher sales volumes) than a bundled rebate involving a biosimilar. Johnson & Johnson’s claim that Pfizer could simply have offered its own bundled rebate involving Inflectra and other Pfizer products seems to have overlooked this fact.

 

Automatic Substitution Laws

The BPCIA specifies that an interchangeable biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”[56] Unlike generic drugs, biosimilars must meet additional statutory criteria to be designated as interchangeable: an expectation of the same clinical result as the reference product and a demonstration of comparable safety and efficacy if a patient switches between the reference product and the biosimilar, as compared to use of the reference product alone.[57] The European Medicines Agency, by contrast, does not promulgate analogous criteria for interchangeability, leaving decisions regarding interchangeability to member nations.[58]

 

In May 2019, FDA made available its final guidance on interchangeability, including recommendations for the design of “switching studies” to support a designation of interchangeability.[59] FDA subsequently released a draft guidance of additional Q&As on biosimilarity and interchangeability in November 2020.[60] In April 2021, drug maker Boehringer Ingelheim released results from a Phase III “switching study” of its Humira biosimilar, adalimumab-adbm (Cyltezo), that it plans to use in support of an application for interchangeability.[61] On July 28, 2021, FDA reached a notable milestone with approval of the first interchangeable biosimilar in the United States: Semglee (insulin glargine-yfgn).[l62] Semglee can be substituted for reference product Lantus without the intervention of a prescriber, and it will serve as a natural experiment of sorts in the biosimilar space that will shed light on the impact of interchangeability on biosimilar uptake and pricing.

 

Yet, individual states, not the FDA, regulate the practice of retail pharmacy, and in response to the BPCIA, at least 45 states and Puerto Rico have passed legislation pertaining to pharmacy-level biosimilar substitution.[63] Automatic substitution laws have greater relevance to biologics and biosimilars dispensed at the pharmacy counter or through a hospital pharmacy than to those administered in a doctor’s office. Nonetheless, a biosimilar typically must be licensed as interchangeable in order for automatic substitution to occur at the pharmacy level. State laws vary with respect to requirements for notice and consent from patients, and with respect to record-keeping requirements when a biosimilar is substituted.[64] For example, in South Carolina, a pharmacist may only substitute an interchangeable biosimilar for the reference product if the patient is advised that the prescriber has authorized the substitution and the patient consents.[65] Conversely, Montana’s legislation lacks a patient consent requirement and is silent on any requirement to even inform the patient of the substitution.[66] Montana does, however, require provider notification. Both state laws require the pharmacist to communicate the substitution to the provider through an electronic record system within five business days.

 

In sum, interchangeability has a gatekeeping function to automatic substitution based on the statutory definition of an interchangeable product, but state automatic substitution laws ultimately control the manner and means of pharmacy-level substitution of biosimilars.

 

Policy Recommendations: Paving a Smoother Path Forward for Biosimilars

This section describes several policy recommendations to address the aforementioned legal obstacles.

Replacing the “Patent Dance”

Limiting the number of patents that can be litigated under the BPCIA to twenty or fewer, as has been proposed in federal bills,[67] promises only a modest improvement, if any, in the timeframe of biosimilar-related patent litigation. Litigation could drag on for years, rendering largely ineffective the patent dance’s attempt to expedite patent resolution before biosimilars reach the market. Policymakers might consider whether some of these delays could be avoided if the BPCIA were amended to replace the patent dance and instead incorporate elements of the Hatch-Waxman Act. Certain elements of the Hatch-Waxman Act’s process may offer a more familiar and workable alternative to the highly contentious and easily circumvented patent dance.

 

Reforming the Patent System

While patent protection spurs pharmaceutical innovation, patents inflict real harms in the subset of cases in which minor secondary patents unduly extend the periods of exclusivity enjoyed by expensive and widely used pharmaceutical drugs. There have been long-standing concerns that patent applications receive only cursory review by patent examiners and that statutory criteria for patentability are not enforced with sufficient stringency.[68],[69] Research has confirmed that the U.S. Patent Office issues patents at a higher rate than does the European Patent Office, which may be due to a combination of lower examination rigor in the United States and differences in standards of patentability.[70] Applying patentability standards to pharmaceutical drugs with greater rigor, particularly the standard of non-obviousness, may help reduce the issuance of problematic secondary patents.

Publicly Listing Biologic Patents

The Purple Book, a publicly available, FDA-maintained database of licensed biologic products, does not presently list patent and exclusivity information, as does its counterpart for small-molecule drugs, the Orange Book. Legally mandating that drug makers provide a complete listing of biologic patents for FDA publication in the Purple Book, and that only listed patents may form the basis of a claim of infringement, can improve transparency and reduce gamesmanship by biologic manufacturers. The Purple Book Continuity Act, which passed the House unanimously in 2019,[71] would require reporting of patent and exclusivity information for all licensed biologic drugs.[72] In the case of biologics, it is crucial to require the listing of all patents that may reasonably be used to protect the biologic product, including patents on manufacturing processes.

 

Promoting Automatic Substitution

Currently, state laws that govern pharmacy practices, not the FDA, determine whether pharmacists may substitute a biosimilar for a prescribed biologic. Thus, U.S. states have an opportunity to increase biosimilar market penetration through automatic substitution laws. Over time, as biosimilars develop a proven track record of safety and efficacy, existing arguments against automatic, pharmacy-level substitution may lose traction.

 

Because most state laws condition substitution on interchangeability, interchangeability in effect functions as a barrier to biosimilar substitution and utilization. Policymakers should consider whether granting a larger set of biosimilars interchangeable status — effectively eliminating the higher evidentiary standard for interchangeability — would not create safety concerns while increasing biosimilar usage. For instance, revisions to the BPCIA making it simpler for biosimilar insulins to demonstrate interchangeability could help address high insulin prices by enabling more rapid approval of additional interchangeable biosimilar insulins that can place further downward pressure on prices. A House bill introduced in September 2020 goes even further; it would make all biosimilar insulins interchangeable with their respective reference products.73] In the meantime, state-level policies that incentivize the prescribing of biosimilars as a first-line treatment option for treatment-naïve patients can help mitigate the impact of interchangeability on biosimilar utilization.

 

Addressing Anticompetitive Practices

Finally, a tougher stance by federal agencies and the courts toward deliberately anticompetitive behavior, such as pay-for-delay deals, bundled rebates, and exclusive dealing, can help ensure fair market conditions for biosimilars to compete. In an opinion piece, former FDA Commissioner Scott Gottlieb called the use of rebates to crowd out biosimilar drugs “anticompetitive” and acknowledged that even some drug makers supported the Trump Administration proposal ending the existing safe harbor for rebates to Medicare Part D plans and pharmacy benefit managers.[74] Several bills in the current Congress prohibit pay-for-delay,[75], [76], [77] and these bills tend to enjoy bipartisan support. It is important that any legislation prohibiting pay-for-delay agreements contain a definition of this practice broad enough to encompass “camouflaged” forms of compensation from the brand to the generic company, and that pay-for-delay deals be prohibited in the context of post-grant opposition proceedings, not just patent infringement lawsuits.

 

Conclusion

Biologics remain key drivers of pharmaceutical spending growth, and consequently, biosimilars will become an increasingly important vehicle to limit spending. As more and more biologic drugs reach the end of their twelve-year period of market exclusivity and key patents expire, biosimilar drug development will blossom as drug companies take advantage of the market opportunity to secure a slice of the market for high-priced biologic therapies. The relatively modest price reduction of biosimilars relative to biologics, often not exceeding 30% of the reference product’s price, makes the potential financial gain to makers of biosimilars quite large. Yet, even a 30% price reduction on very high-priced therapies means that patients and payors stand to save considerable sums from biosimilar utilization.

 

Various legal factors contribute to the poor market availability of biosimilars in the United States, intellectual property protections chief among them. Three of the five legal obstacles examined here implicate patents, underscoring the importance of patent issuance and patent litigation to whether and when biosimilars enter the market. More scrutiny of the patents that have been issued on biologic drugs is sorely needed to assess whether invalid patents are being issued at an unacceptably high rate. Once issued, patents are presumed valid, and patent infringement litigation — such as that initiated with the BPCIA’s patent dance or litigation that takes place after a drug maker declines to engage in the patent dance — can delay when a biosimilar enters the market. Settlement of this litigation, however, is not preferable to a court judgment when the terms of the settlement are anticompetitive, as with unlawful pay-for-delay deals. Antitrust law with respect to pay-for-delay is an important and evolving area of the law that holds tremendous potential to either forestall or facilitate timely entry of biosimilars. The associated litigation should be closely watched.

 

Though contractual in nature, bundled rebates and exclusive deals for formulary placement implicate antitrust concerns, and here too the courts are able to deliver critical holdings that could reshape the landscape of what constitutes legitimate competitive contractual dealings. Finally, state laws dictating biosimilar substitution policies at the pharmacy level may be the most readily attainable means to advancing biosimilar uptake in the short term. State legislatures should act accordingly to develop policies that do not impose onerous burdens on biosimilar substitution while ensuring patient safety.

 

In sum, the manner in which courts, states, and Congress address these unfolding legal questions has the potential to further stymie biosimilars or, alternatively, to level the playing field for emerging biosimilar competitors. The fate of biosimilars in the United States will depend principally on how judges and policymakers come down on each of these legal and regulatory issues.

Table

Table 1. Biosimilars licensed in the United States (2015 – August 2021), manufacturer, date of FDA licensure, and whether each product is on the market in the United States.  (Reference products are shown in bold.)

 

U.S. Nonproprietary

Name

 

Trade Name

 

 

 

Manufacturer

 

 

Date of FDA Licensure

 

Marketed? (Yes/No)

 

adalimumab

Humira

AbbVie

2002

Yes

adalimumab-atto

Amjevita

Amgen

Sept. 2016

Noi

adalimumab-adbm

Cyltezo

Boehringer Ingelheim

Aug. 2017

Noi

adalimumab-adaz

Hyrimoz

Sandoz (Novartis)

Oct. 2018

Noi

adalimumab-bwwd

Hadlima

Samsung Bioepis

July 2019

Noi

adalimumab-afzb

Abrilada

Pfizer

Nov. 2019

Noi

adalimumab-fkjp

Hulio

Mylan

July 2020

Noi

 

 

 

 

 

bevacizumab

Avastin

Genentech (Roche)

2004

Yes

bevacizumab-awwb

Mvasi

Amgen

Sept. 2017

Yes

bevacizumab-bvzr

Zirabev

Pfizer

June 2019

Yes

 

 

 

 

 

epoetin alfa

Epogen, Procrit

Amgen, Janssen

1989

Yes

epoetin alfa-epbx

Retacrit

Pfizer

May 2018

Yes

 

 

 

 

 

etanercept

Enbrel

Amgen

1998

Yes

etanercept-szzs

Erelzi

Sandoz (Novartis)

Aug. 2016

No

etanercept-ykro

Eticovo

Samsung Bioepis

Apr. 2019

No

 

 

 

 

 

filgrastim

Neupogen

Amgen

1991

Yes

filgrastim-sndz

Zarxio

Sandoz (Novartis)

Mar. 2015

Yes

filgrastim-aafi

Nivestym

Pfizer

July 2018

Yes

 

 

 

 

 

infliximab

Remicade

Janssen (Johnson & Johnson)

1998

Yes

infliximab-dyyb

Inflectra

Pfizer

Apr. 2016

Yes

infliximab-abda

Renflexis

Samsung Bioepis, Merck

May 2017

Yes

infliximab-qbtx

Ixifi

Pfizer

Dec. 2017

Noii

infliximab-axxq

Avsola

Amgen

Dec. 2019

Yes

 

 

 

 

 

insulin glargine

Lantus

Sanofi

2000

Yes

insulin glargine-yfgn

Semglee

Mylan

July 2021

Yes

 

 

 

 

 

pegfilgrastim

Neulasta

Amgen

2002

Yes

pegfilgrastim-jmdb

Fulphila

Mylan, Biocon

June 2018

Yes

pegfilgrastim-cbqv

Udenyca

Coherus BioSciences

Nov. 2018

Yes

pegfilgrastim-bmez

Ziextenzo

Sandoz (Novartis)

Nov. 2019

Yes

pegfilgrastim-apgf

Nyvepria

Pfizer

June 2020

No

 

 

 

 

 

rituximab

Rituxan

Genentech (Roche)

1997

Yes

rituximab-abbs

Truxima

Celltrion

Nov. 2018

Yes

rituximab-pvvr

Ruxience

Pfizer

July 2019

Yes

rituximab-arrx

Riabni

Amgen

Dec. 2020

Yes

 

 

 

 

 

trastuzumab

Herceptin

Genentech (Roche)

1998

Yes

trastuzumab-dkst

Ogivri

Mylan, Biocon

Dec. 2017

Yes

trastuzumab-dttb

Ontruzant

Samsung Bioepis

Jan. 2019

Yes

trastuzumab-pkrb

Herzuma

Celltrion, Teva

Dec. 2018

Yes

trastuzumab-qyyp

Trazimera

Pfizer

Mar. 2019

Yes

trastuzumab-anns

Kanjinti

Amgen, Allergan

June 2019

Yes

i Biosimilars to Humira are expected to launch in the United States in 2023.

ii Pfizer announced in 2017 that it would not launch Ixifi because another Pfizer infliximab biosimilar, Inflectra, was already on the market in the United States.

References

[1] United States Government Accountability Office. (2015). Medicare Part B: Expenditures for new drugs concentrated among a few drugs, and most were costly for beneficiaries. https://www.gao.gov/assets/gao-16-12.pdf

 

[2] Nguyen, N. X., & Sheingold, S. (2020). Medicare Part B Drugs: Trends in spending and utilization, 2006-2017. Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services. https://aspe.hhs.gov/system/files/pdf/264416/Part-B-Drugs-Trends-Issue-Brief.pdf

 

[3] McCormick, N., Wallace, Z. S., Sacks C. A., Hsu J., & Choi H. K. (2020). Decomposition analysis of spending and price trends for biologic antirheumatic drugs in Medicare and Medicaid. Arthritis & Rheumatology, 72(2), 234-241. https://doi.org/10.1002/art.41138

 

[4] Biologics Price Competition and Innovation Act, 42 U.S.C. § 262(k)(4)(A) (2019).  https://www.law.cornell.edu/uscode/text/42/262

 

[5] Biologics Price Competition and Innovation Act, 42 U.S.C. § 262(k)(2) (2019).  https://www.law.cornell.edu/uscode/text/42/262

 

[6] United States Food & Drug Administration. (2020, December 17). Biosimilar product information. Retrieved May 14, 2021, from https://www.fda.gov/drugs/biosimilars/biosimilar-product-information

 

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[13] Biologics Price Competition and Innovation Act, 42 U.S.C. § 262(l)(3) (2019).  https://www.law.cornell.edu/uscode/text/42/262

 

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[15] Sandoz Inc. v. Amgen Inc., 137 S. Ct. 1664, 1676 (2017).

 

[16] Complaint at 4, ¶ 6-7, Genentech, Inc. v. Amgen Inc., No. 17-cv-00165 (D. Del. Feb. 15, 2017).

 

[17] Amgen Inc. v. Hospira, Inc., 944 F.3d 1327 (Fed. Cir. 2019).

 

[18] Biologics Price Competition and Innovation Act, 42 U.S.C. § 262(l)(8)(A) (2019).  https://www.law.cornell.edu/uscode/text/42/262

 

[19] Sandoz Inc., 137 S. Ct. at 1677.

 

[20] Biologics Price Competition and Innovation Act, 42 U.S.C. § 262(k)(7)(A) (2019).  https://www.law.cornell.edu/uscode/text/42/262

 

[21] Hospira, Inc., 944 F.3d at 1339–40.

 

[22] Sandoz Inc., 137 S. Ct. at 1670.

 

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[29] I MAK. (2020, October). Overpatented, overpriced special edition: Humira. https://www.i-mak.org/wp-content/uploads/2020/10/i-mak.humira.report.3.final-REVISED-2020-10-06.pdf

 

[30] Sagonowsky, E. (2021, May 3). The top 20 drugs by worldwide sales in 2020. Fierce Pharma. https://www.fiercepharma.com/special-report/top-20-drugs-by-2020-sales

 

[31] Norman, P. (2016). Humira: The impending patent battles over adalimumab biosimilars. Pharmaceutical Patent Analyst, 5(3), 141-145. https://doi.org/10.4155/ppa-2016-0002

 

[32]Gunn, H. (2019, May 14). AbbVie and Boehringer Ingelheim settle adalimumab biosimilar patent disputes. Goodwin. https://www.bigmoleculewatch.com/2019/05/14/abbvie-and-boehringer-ingelheim-settle-adalimumab-biosimilar-patent-disputes/

 

[33] Dunn, A. (2019, May 14). With Boehringer settlement, AbbVie completes Humira sweep. Biopharma Dive.  https://www.biopharmadive.com/news/abbvie-boehringer-ingelheim-settle-humira-patent-biosimilar/554729/

 

[34] I MAK. (n.d.). Overpatented, overpriced special edition: Enbrel. http://www.i-mak.org/wp-content/uploads/2018/12/i-mak.enbrel.report-2018-11-30F.pdf.

 

[35] Wilmot, C. (2020, October 7). Federal Circuit refuses to reconsider its panel decision finding no common ownership of Immunex’s Enbrel patent. JD Supra. https://www.jdsupra.com/legalnews/federal-circuit-refuses-to-reconsider-94131

 

[36] Immunex Corp. v. Sandoz Inc., 964 F.3d 1049, 1053 (Fed. Cir. 2020).

 

[37] Beasley, D. (2019, August 9). Amgen wins U.S. patent battle on arthritis drug Enbrel, thwarting Novartis. Reuters. https://www.reuters.com/article/us-usa-court/amgen-wins-u-s-patent-battle-on-arthritis-drug-enbrel-thwarting-novartis-idUSKCN1UZ2A6

 

[38] Immunex, 964 F.3d at 1062-63.

 

[39] Federal Trade Commission. (2010). Pay-for-delay: How drug company pay-offs cost consumers billions. https://www.ftc.gov/sites/default/files/documents/reports/pay-delay-how-drug-company-pay-offs-cost-consumers-billions-federal-trade-commission-staff-study/100112payfordelayrpt.pdf

 

[40] Federal Trade Commission. (n.d.). Medicare Prescription Drug and Improvement Act requires drug companies to file certain agreements with the Federal Trade Commission and the U.S. Department of Justice. https://www.ftc.gov/system/files/attachments/pharmaceutical-agreement-filings/mma_pharmaceutical_agreement_filing_instructions_6-6-19.pdf

 

[41] FTC v. Actavis, Inc., 570 U.S. 136, 149, 158-59 (2013).

 

[42] Federal Trade Commission. (n.d.). Agreements filed with the Federal Trade Commission under the Medicare Prescription Drug, Improvement, and Modernization Act of 2003: Overview of agreements filed in FY 2016. https://www.ftc.gov/system/files/documents/reports/agreements-filled-federal-trade-commission-under-medicare-prescription-drug-improvement/mma_report_fy2016.pdf

 

[43] Carrier, M. A. (2014). Payment after Actavis. Iowa Law Review, 100(1), 7-49. https://ilr.law.uiowa.edu/print/volume-100-issue-1/payment-after-actavis

 

[44] Karas, L., Anderson, G. F., & Feldman, R. (2020). Pharmaceutical “pay-for-delay” reexamined: A dwindling practice or a persistent problem? Hastings Law Journal, 71(4), 959-974. https://www.hastingslawjournal.org/pharmaceutical-pay-for-delay-reexamined-a-dwindling-practice-or-a-persistent-problem

 

[45] In re Humira (Adalimumab) Antitrust Litig., 465 F. Supp. 3d 811, 840 (N.D. Ill. 2020).

 

[46] Xin, X. (2021, April 16). 7th Circuit hears oral arguments in Humira “patent thicket” antitrust case. JD Supra.  https://www.jdsupra.com/legalnews/7th-circuit-hears-oral-arguments-in-9057194.

 

[47] Complaint at 21, 26-28, Pfizer Inc. v. Johnson & Johnson, No. 17-cv-04180 (E.D. Pa. Sept. 20, 2017).

 

[48] Complaint at 41, Pfizer Inc. v. Johnson & Johnson, No. 17-cv-04180 (E.D. Pa. Sept. 20, 2017).

 

[49] Reply Memorandum of Law in Further Support of the Defendants’ Motion to Dismiss at 8-10, Pfizer Inc. v. Johnson & Johnson, No. 17-cv-04180 (E.D. Pa. Feb. 1, 2018).

 

[50] Hagen, T. (2020, October 14). Amgen 2020 biosimilar report provides market share, ASP info.  American Journal of Managed Care: The Center for Biosimilars. https://www.centerforbiosimilars.com/view/amgen-2020-biosimilar-report-provides-market-share-asp-info

 

[51] Pfizer Inc. v. Johnson & Johnson, 333 F. Supp. 3d 494, 505 (E.D. Pa. 2018).

 

[52 Konnath, H. (2021, July 21). J&J settles Pfizer’s antitrust suit over Remicade biosimilar. Law360. https://www.law360.com/competition/articles/1405274/j-j-settles-pfizer-s-antitrust-suit-over-remicade-biosimilar

 

[53] Exec. Order No. 14036, 3 C.F.R. 36997 (2021). https://www.federalregister.gov/documents/2021/07/14/2021-15069/promoting-competition-in-the-american-economy

 

[54] Hovenkamp, E., & Hovenkamp, H. J. (2008). Exclusionary bundled discounts and the Antitrust Modernization Commission. Faculty Scholarship at Penn Law, 1773, 1-40. https://scholarship.law.upenn.edu/faculty_scholarship/1773

 

[55] Pfizer, 333 F. Supp. 3d at 503.

 

[56] Biologics Price Competition and Innovation Act, 42 U.S.C. § 262(i)(3) (2019).  https://www.law.cornell.edu/uscode/text/42/262

 

[57i] Biologics Price Competition and Innovation Act, 42 U.S.C. § 262(k)(4) (2019).  https://www.law.cornell.edu/uscode/text/42/262

 

[58] European Medicines Agency & the European Commission. (2019). Biosimilars in the EU: Information guide for healthcare professionals. https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf

[59] United States Department of Health and Human Services, Food and Drug Administration. (2019). Considerations in demonstrating interchangeability with a reference product: Guidance for industry. https://www.fda.gov/media/124907/download

 

[60] United States Department of Health and Human Services, Food and Drug Administration. (2020). Biosimilarity and interchangeability: Additional draft Q&As on biosimilar development and the BPCI Act. https://www.fda.gov/media/143847/download

 

[61] Boehringer Ingelheim. (2021, April 23). VOLTAIRE-X phase III data in patients with moderate-to-severe chronic plaque psoriasis support interchangeability application. https://www.boehringer-ingelheim.us/press-release/voltaire-x-phase-iii-data-patients-moderate-severe-chronic-plaque-psoriasis-support

 

[62] U.S. Food & Drug Administration.  (2021, July 28).  FDA Approves First Interchangeable Biosimilar Insulin Product for Treatment of Diabetes.  https://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes

 

[63] Cauchi, R. (2019, May 3). State laws and legislation related to biologic medications and substitution of biosimilars. National Conference of State Legislatures. https://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx

 

[64] Gabay, M. (2017). Biosimilar substitution laws. Hospital Pharmacy, 52(8), 544-545. https://doi.org/10.1177/0018578717726995

 

[65] S.C. Code Ann. § 39-24-40 (2017).

 

[66] Mont. Code Ann. § 37-7-505 (2017).

 

[67] Affordable Prescriptions for Patients Act of 2019, S. 1416, 116th Cong. (2019). https://www.congress.gov/116/bills/s1416/BILLS-116s1416rs.pdf

 

[68] Sag, M., & Rohde, K. (2006). Patent reform and differential impact. Minnesota Journal of Law, Science & Technology, 8(1), 1-93. https://scholarship.law.umn.edu/mjlst/vol8/iss1/3

 

[69] Lemley, M., Lichtman, D., & Sampat, B. (2006). What to do about bad patents? Regulation, 28(4), 10-13. https://www.cato.org/sites/cato.org/files/serials/files/regulation/2005/12/v28n4-noted.pdf#page=3

 

[70] Quillen, C. D., & Webster, O. H. (2006). Continuing patent applications and the U.S. Patent and Trademark Office — Updated. The Federal Circuit Bar Journal, 15(4), 635-677.

 

[71] House Committee on Energy & Commerce. (2019, May 8). Pallone & Eshoo on House passage of bills increasing the accuracy & transparency of FDA’s prescription drug databases. https://energycommerce.house.gov/newsroom/press-releases/pallone-eshoo-on-house-passage-of-bills-increasing-the-accuracy-transparency

 

[72] Purple Book Continuity Act of 2020, amendment to H.R. 1520, 116th Cong. (2020). https://www.govinfo.gov/content/pkg/BILLS-116hr1520eas/pdf/BILLS-116hr1520eas.pdf

 

[73] Biosimilar Insulin Access Act of 2020, H.R. 8190, 116th Cong. (2020). https://www.congress.gov/116/bills/hr8190/BILLS-116hr8190ih.pdf

 

[74] Gottlieb, S. (2019, August 25). Don’t give up on biosimilars – Congress can give them a boost. Wall Street Journal. https://www.wsj.com/articles/dont-give-up-on-biosimilarscongress-can-give-them-a-boost-11566755042

 

[75] Protecting Consumer Access to Generic Drugs Act of 2021, H.R. 153, 117th Cong. (2021). https://www.congress.gov/117/bills/hr153/BILLS-117hr153ih.pdf

 

[76] Lower Costs, More Cures Act of 2021, H.R. 19, 117th Cong. (2021). https://www.congress.gov/117/bills/hr19/BILLS-117hr19ih.pdf

 

[77] Preserve Access to Affordable Generics and Biosimilars Act, S. 1428, 117th Cong. (2021).  https://www.congress.gov/117/bills/s1428/BILLS-117s1428is.pdf

About the Author

Laura Karas, MD, MPH

Laura Karas, MD, MPH is a third-year J.D. candidate at Harvard Law School.

Rachel Sachs, JD, MPH

Rachel Sachs, JD, MPH is the Treiman Professor of Law at the Washington University School of Law.

Gerard Anderson, PhD

Gerard Anderson, PhD is with the Johns Hopkins Bloomberg School of Public Health, Department of Health Policy and Management, Baltimore, MD.