Biosimilar or Biodifferent: How a Name Will Shape the Market for Biosimilars

Whether biosimilars and interchangeable biologics should share the same nonproprietary name as their reference products has been hotly debated. At issue, ultimately, is the degree to which biosimilars will introduce price competition into the US marketplace for biologics and expand access to these medicines. The United States spends the most on biologics,¹ and thus the opportunities to reduce healthcare costs are enormous. So, too, are the commercial opportunities: it is predicted that by 2016 eight of the top 10 bestselling drug products will be biologics, and biologics with combined revenues of $79 billion are expected to go off-patent by 2018.² Thus, as patents covering biologics expire, companies will seek to market their own versions of the originators’ biologics, as biosimilars, interchangeable biologics, or “bio betters.” Yet a number of scientific, economic, legal, and political hurdles must be overcome by companies wishing to market follow-on biologics.

First, the FDA’s approval standards are rigorous: a biosimilar must be “highly similar” to the reference product and there must be “no clinically meaningful differences” between the biosimilar and the reference product. Interchangeable biologics must meet an even higher standard.³ Second, because of these rigorous approval standards, developing a biosimilar is expensive—it has been estimated that developing a biosimilar of a complex biologic, such as a monoclonal antibody, could cost more than $100 million and take more than five years.1 Third, aspiring biosimilar manufacturers are confronted with a patchwork of varying state laws governing the requirements for substituting a biosimilar for a prescribed reference product. Finally, even the seemingly simple question of how to name a biosimilar remains unanswered and has become another source of difficulty and dispute.

The law that governs the approval pathways for follow-on biologics— the Biologics Price Competition and Innovation Act (the “Biologics Act”)—fails to address how biosimilars should be named. Naming of products is less of an issue under the Hatch-Waxman Act, which provides a regulatory pathway for generic small-molecule pharmaceuticals. Under the Hatch-Waxman Act, safe and effective generic drugs can obtain approval from the FDA to enter a market without replicating all of the expensive testing required for the approval of a branded drug. To be approved under the Hatch-Waxman Act, the applicant must show that its generic drug product is “bioequivalent” to the branded drug product. And because an FDA-approved generic drug has the identical active substance and is “bioequivalent” to its brand-name counterpart, the generic drug is given the same active ingredient name (ie, the same nonproprietary name) as the branded product.

But biosimilars are not generic versions of existing biologics. Whereas generic small-molecule drugs contain an active ingredient that is identical to that in the brand product, a biosimilar may contain an active ingredient that is slightly different from the reference product, as long as the differences are not clinically meaningful. Differences between a biosimilar and its reference product may arise because of, for example, differences in the cell lines and processes used during manufacturing. Even slight variations in temperature or chemical media can result in differences in the final products. Thus, approved biosimilars will be highly similar to their reference products, but unlike generic drugs, not identical. This potential for variation is a source of concern for manufacturers and regulators because even minor differences in a protein can potentially affect its efficacy and side effect profile. Some stakeholders, such as Amgen, have therefore argued that the naming of generic drugs under the Hatch-Waxman Act should not serve as a model for the naming of biosimilars. By contrast, generic drug makers generally want biosimilars to be named like generics, ie, the biosimilar product would have the same nonproprietary name as the reference products.

Because no law dictates how biosimilars should be named, numerous stakeholders, including pharmaceutical companies such as Amgen, Genentech, Janssen, Momenta, Novartis, as well as non-profit associations such as the Biotechnology Industry Organization (BIO), the Generic Pharmaceutical Association (GPhA), and the Pharmaceutical Research and Manufacturers of America (PRMA) have submitted citizen petitions or responses to citizen petitions, requesting that the FDA either (1) allow biosimilars to share the same nonproprietary name as their reference products, or (2) require biosimilars to have distinct nonproprietary names. The arguments on each side of the debate have focused primarily on three issues: pharmacovigilance, patient safety, and the naming requirements that international regulatory agencies have so far issued.

Nonproprietary Names and Pharmacovigilance

Amgen, BIO, Genentech, Janssen, and PhRMA assert that allowing a biosimilar to have the same nonproprietary name as its reference product would impair pharmacovigilance. Their reasoning can be summarized as follows:

• If adverse events were to identify a biologic solely by nonproprietary name, the shared names would complicate, if not prevent, tracing the adverse report to a specific product. Amgen explained that “[b]ecause FDA’s spontaneous reporting/postmarket surveillance system does not encompass the separate tracking of [products] sharing the same non-proprietary name to be separately tracked, biosimilars with the same non-proprietary names but potentially different immunogenic profiles will be difficult to distinguish, hampering immunogenicity tracking and optimal pharmacovigilance.”
• Shared names may mask an increase or qualitative change in adverse events as to one product but not others. PhRMA argued that pooling of adverse events by shared name “may mask a small, but nevertheless statistically significant, rate increase for a particular product, and importantly, real public health consequences.”
• If a patient is switched from a reference biologic to a biosimilar without a physician knowing of the switch, the physician may not know the particular product administered and may thus submit an adverse event report that incorrectly identifies the product administered to the patient.
• Shared names may lead to more patients being switched from one product to another; this switching would further complicate efforts to determine the product responsible for an adverse event. Janssen offered as an example the incidence of pure red cell aplasia in Thailand caused by an epoetin alfa biologic product. Because patients in Thailand were switched among the multiple epoetin alfa products available, it was difficult to determine the particular product responsible for the pure red cell aplasia side effects.

GPhA, Momenta, and Novartis take the opposite view, contending that requiring distinct names for biosimilars is unnecessary for—and may impair—pharmacovigilance, arguing that:

• Requiring unique nonproprietary names would segregate the safety data for brand and biosimilar products, making it more difficult to detect rare adverse event signals across classes of products.
• A well-established process exists to track quality and adverse events that does not rely primarily on nonproprietary names, but instead uses a product’s brand name, manufacturer, lot number, and National Drug Code (NDC). The NDC reflects the manufacturer of the product; the active ingredient and its strength, dosage form, and formulation; and the package size.⁴ The NDC is unique to the product and manufacturing batch, and can be used to track biosimilars. GPhA contends that the NDC may be the most precise method available for tracking drug products.
• Batches of a brand product are sold interchangeably and have the same name despite product “drift” that occurs over time. The FDA has authorized originator manufacturers to modify a biologic’s manufacturing process and market a biologic that has minor changes and differences that are not clinically meaningful— without requiring a change in nonproprietary name. The originator must demonstrate that the post-change biologic is “comparable” to the pre-change version. The standards for comparability and biosimilarity are largely the same. Novartis and GPhA have thus asserted that biosimilars, as highly similar to their reference products, should share nonproprietary names just as biologics maintain their nonproprietary names despite changes in the product over time.
• Competing brand products in the same class of biologics share a nonproprietary name. The FDA routinely allows originator biologic products in the same class to have the same nonproprietary name, even though they were approved under different applications, manufactured by different companies, and manufactured using different methods. For example, Bayer’s Kogenate^® FS, Genetics Institute’s ReFacto^®, and Baxter’s Recombinate^® are all recombinant factor VIII treatments made by different manufacturers but share the same nonproprietary name—“antihemophilic factor (recombinant).” In its citizen petition, Novartis has identified numerous other such examples.
• In Europe, where biosimilars have been in the market since 2006, no tracking issues have arisen from biosimilars sharing nonproprietary names.

Nonproprietary Names and Patient Safety

Amgen, Genentech, Janssen, and PhRMA have asserted that shared names could undermine patient safety, pointing out that:

• Shared names could lead to greater switching among products. For example, if a physician typically prescribes medications by nonproprietary name and does so for a biologic, the patient may inadvertently be switched to a different product. This switching could increase the risk to patients if the FDA has not deemed the new product interchangeable with the old product. Janssen contends that, for example, if two products each have a 5% risk of immunogenicity that are caused by different factors, “[s]witching patients who have not experienced immunogenicity on one product to the other product could expose those patients to an additional risk of immunogenicity—a cumulative risk of up to 10%, which is a greater level of risk than is associated with either product without switching.”
• Shared names could lead to inadvertent switching to a product that has not been approved for the indication for which the patient seeks treatment. For example, Janssen explained that the FDA may approve a biosimilar for only a subset of the uses for which the reference product is approved.

GPhA, Momenta, and Novartis have taken the opposite view, offering several arguments in support of the proposition that requiring biosimilars to have unique nonproprietary names would jeopardize patient safety:

• Requiring different nonproprietary names could, Novartis has asserted, inaccurately suggest that a biosimilar has meaningful clinical differences as compared to its reference produce, even though the FDA has determined that the biosimilar and its reference product are “highly similar.” The resulting clinical confusion may lead to prescribing errors, compromise patient access to followon biologics, cause patients to potentially go untreated, and disaggregate adverse event data for the products, which could hinder rapid identification of class effects and rare safety signals.
• Just as requiring a biosimilar to have a different nonproprietary name could suggest that it has meaningful clinical differences, this requirement could lead prescribers to infer that two originator biologics that share the same nonproprietary name are interchangeable and produce the same clinical outcome. A prescriber may thus switch a patient from one originator biologic to another originator biologic with the same nonproprietary name, even though the FDA may not have deemed them interchangeable. In fact, Novartis has asserted that in one case, two such originator biologics “explicitly failed compatibility.”⁵

International “Consensus” on Nonproprietary Names

Although the FDA (and other agencies, such as Health Canada), have not yet issued guidelines on the naming of biosimilars, other regulatory agencies have. Amgen, Genentech, Janssen, and PhRMA contend that the guidelines from these agencies reflect an emerging international consensus that biosimilars should have distinguishable nonproprietary names. By contrast, BIO acknowledges that no such consensus yet exists. The positions of some international agencies on this issue are outlined briefly below.

In 2004, the European Union became the first jurisdiction to authorize the establishment of a pathway for the approval of biosimilars. Most biosimilars approved to date in the European Union have the same nonproprietary name as the reference product. For example, Remicade (the reference biologic made by Janssen) and Remsima (a biosimilar made by Celltrion) have the same nonproprietary name: infliximab. In contrast, Japan and Australia require distinguishable nonproprietary names. In Japan, the nonproprietary names and brand names of biosimilars must be readily distinguishable from the names of their reference products, and from related biosimilars. For instance, on March 24, 2014, the Japanese regulatory agency approved Sandoz’s biosimilar of filgrastim. Sandoz’s product in Japan must be marketed with the brand name “Filgrastim BS Injection 75 μg/150 μg/ 300 μg Syringe Sandoz”—the “BS” indicating that the product is a biosimilar.

This product must also have a unique nonproprietary name that includes the term “Biosimilar” and an order number, indicating whether Sandoz’s biosimilar is the first, second, or third biosimilar of filgrastim. In Australia, regulators have proposed that a biosimilar’s name comprise (1) the Australian Biological Name of the reference product, (2) followed by the word “sim,” and (3) a unique three-letter identifier.⁶ For example, a biosimilar to the monoclonal antibody infliximab could theoretically have a nonproprietary name such as “infliximab simfam.”

Arguments Concerning the “Anticompetitive Effects” of Nonproprietary Names

Momenta, a biotechnology company focused on developing biosimilars and other complex products, has asserted that the motivation for suggesting that biosimilars have distinguishable nonproprietary names comes not from pharmacovigilance or patient safety reasons, as outlined above, but from commercial interests. Earlier this year, Momenta urged the Federal Trade Commission to oppose as anti-competitive any efforts to require distinguishable nonproprietary names. Distinguishable nonproprietary names, Momenta argued, would hinder or prevent competition from more affordable biosimilar and interchangeable biologic products. Sales representatives of brand biologics could, for example, promote use of the brand’s unique nonproprietary name to reduce substitution. To overcome these tactics, Momenta contends that companies offering biosimilars would have to employ expensive branding and marketing campaigns, thereby increasing the costs of biosimilars and reducing the savings to patients. One objective of the Biologics Act, like the Hatch-Waxman Act, is to encourage price competition and realize savings for consumers while fostering an environment for innovation. Whether economic considerations will influence how the FDA resolves the debate over naming remains to be seen.

What’s Next?

Biosimilars present an opportunity to provide greater access to biologic therapy and to control healthcare costs. Indeed, the Congressional Budget Office (CBO) has estimated that follow-on biologic competition leading to lower biologics prices could save consumers billions of dollars each year.⁷ Whether companies will pursue biosimilars and thus provide lower-cost biosimilars to patients may depend in part on whether the FDA allows follow-on biologics to have the same nonproprietary name as the reference product or requires unique nonproprietary names for each product. The numerous citizen petitions and responses reflect the importance of this issue to the industry. FDA has announced that it plans to issue guidance on this issue shortly. This announcement is just in time, as on July 24, 2014, Sandoz became the first company to announce that the FDA has accepted its application for a biosimilar.⁸ How the FDA settles this naming question will likely affect investment in and access to follow-on biologics.

References:

1. Grabowski H, et al. Regulatory and Cost Barriers Are Likely to Limit Biosimilar Development and Expected Savings in the Near Future. Health Affairs. 2014;33(6):1048-1057.
2. Global Generics Interest Group. Generating value in generics: Finding the next five years of growth. McKinsey & Co. 2013. Available at: http://www.mckinsey.com/~/media/mckinsey/ dotcom/client_service/Pharma%20and%20Medical%20Products/PMP%20NEW/PDFs/ Generating_value_in_generics_June%202013.ashx. Accessed August 22, 2014.
3. US Food and Drug Administration. Guidance, Compliance & Regulatory Information. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ ucm215089.htm. Accessed August 22, 2014.
4. US Food and Drug Administration. Drug Approvals and Databases. Available at: http:// www.fda.gov/drugs/informationondrugs/ucm142438.htm. Accessed August 22, 2014.
5. McCamish M, Gallagher AM, Orloff J. Biosimilar by Name and Biosimilar by Nature. The RPM Report. 2013:1-8. Available at http://www.sandoz-biosimilars.com/cs/groups/public/@ sbs_com/documents/document/n_prod_844294.pdf. Accessed August 22, 2014.
6. Australian Government Department of Health. Therapeutic Goods Administration. Evaluation of biosimilars. Naming Conventions for Biosimilars. Available at: http://www.tga. gov.au/industry/pm-argpm-biosimilars-10.htm#.U5CxOvldVBk. Accessed August 22, 2014.
7. Congressional Budget Office Cost Estimate. S. 1695: Biologics price competition and innovation act of 2007. 2008:5. Available at: http://www.cbo.gov/sites/default/files/ cbofiles/ftpdocs/94xx/doc9496/s1695.pdf. Accessed August 22, 2014.
8. Novartis Media Release. FDA accepts Sandoz application for biosimilar filgrastim. 2014. Available at: http://www.novartis.com/newsroom/media-releases/en/2014/1835571.shtml. Accessed August 22, 2014.

William Jameshas focused his practice on patent litigation related to pharmaceutical and biotechnology products. He has significant experience with Hatch-Waxman litigations, representing both plaintiffs and defendants, including first-to-file cases and multi-defendant ANDA drug challenges.

Thomas Lavery is an associate at Goodwin Procter LLP. He was previously with Kenyon & Kenyon LLP. Mr. Lavery focuses his practice on patent litigation related to pharmaceutical and biotechnology products. He has significant experience with Hatch-Waxman litigations, representing both plaintiffs and defendants, including first-to-file cases and multi-defendant ANDA drug challenges. He also prosecutes patents, provides strategic counseling on biosimilar and biologic products, and prepares validity, infringement, and freedom-tooperate opinions. Mr. Lavery can be reached at [email protected] or 212.459.7160.