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Citing Concerns, FDA Proposes Suffixes For All Biologics, Not Only Biosimilars

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By Angela Maas, Managing Editor
September 2015Volume 12Issue 9

More than five years after the Biologics Price Competition and Innovation Act of 2009 (BPCIA) created the 351(k) approval pathway for biosimilars, the FDA finally released long-awaited guidance on the naming of these products. But while most of the prerelease discussion focused solely on how biosimilars would be treated, the FDA took a more expansive approach, proposing the addition of a four-letter suffix to the nonproprietary names of all biologics. Along with the proposed guidance the agency also on Aug. 27 released a proposed rule that laid out how those suffixes would be applied to certain products (see box, p. 9).

In guidance titled Nonproprietary Naming of Biological Products (80 Fed. Reg. 52296, Aug. 28, 2015), the FDA proposes that both reference products and biosimilars share nonproprietary names indicating the core substance, but that each product has a four-letter, FDA-designated suffix attached with a hyphen that is unique to each product but otherwise has no meaning. This would apply to biologics already on the U.S. market, as well as ones yet to launch. The agency also is seeking feedback on a variety of questions, including whether a suffix based on the name of the company that owns the drug’s license should be used instead of a meaningless one and whether an interchangeable biosimilar should have a distinct suffix or should share that of its reference product.

FDA Wants Suffixes for All Biologics

In an Aug. 27 blog, Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research, and Karen Midthun, M.D., director of the FDA’s Center for Biologics Evaluation and Research, explained that the proposed naming approach “seeks to address two main issues: to help prevent inadvertent substitution (which could lead to medication errors) of biological products that are not determined to be interchangeable by the FDA; and, to support safety monitoring of all biological products after they are on the market, by making it easier to accurately track usage of biological products in all settings of care, such as outpatient, hospital, and pharmacy settings.”

One industry expert who declines to be identified tells SPN that it’s “difficult to work out whether what’s being proposed fixes” the problems that the FDA mentions. “If the issue is that the current [data tracking] systems do what” they are designed to do, “but data is not input accurately,…this doesn’t solve the problem” that there are “not complete and accurate records in different settings of care.…FDA would appear to be assuming 100% accuracy in each setting.” The agency, maintains the source, “is solving a problem that is based in inaccuracy or incompleteness of records,” and for that reason, “I have serious skepticism that this will work.…[The FDA is] replacing a known but very small risk with something of an unknown risk.”

Another potential issue is that many of the stakeholders that will have to implement systems to accommodate the new names are not overseen by the FDA, so there is a danger that they are not aware that changes may need to be made, says the source. “Traditionally the people who are ordering, prescribing and dispensing” biologics are “not regulated by the FDA.” But this change stands to affect “anybody in any setting who uses any of these products.”

Beyond this, the approach creates additional issues, says the unnamed source. For one, it “changes the fundamental role of a nonproprietary name.…A unique nonproprietary name by definition is proprietary…because it applies to only one product.…You’re essentially recreating a brand name,” which means that each biologic will have two unique names. This isn’t necessarily an issue, but “you need the data systems” to support this so that products that should be grouped together are in fact grouped together — such as all the filgrastims — but still indicate the brand and nonproprietary names of each: Neupogen (filgrastim), Zarxio (filgrastim-sndz) and Granix (tbo-filgrastim). Current databases do not have a mechanism for two identifiers of a product on the market, which is a problem because it’s “essential” that the “systems be designed and able to cope with what the FDA proposes.”

The National Council for Prescription Drug Programs (NCPDP), a not-for-profit American National Standards Institute (ANSI)-accredited Standards Development Organization, noted in a June 2014 letter to then FDA Commissioner Margaret Hamburg, M.D., that “While the [drug] compendia can accommodate most data needs, we caution that in making changes to the current databases and the [standard operating procedures] by which they are developed, maintained, and used takes time and resources. This can result in confusion, errors, and misunderstanding, resulting in a very real risk to patients, during any transition.”

Since 1952, the World Health Organization has overseen a globally recognized system that develops International Nonproprietary Names (INNs) based on active pharmaceutical ingredients — a system that the FDA has followed up until now.

NCPDP noted in a pair of 2015 letters that the “FDA’s deviation from standard naming practices and previously established International Nonproprietary Names (INNs) and [United States Adopted Names] has caused great confusion and inconsistencies in preferred names” among federal agencies that maintain the Federal Medication Terminologies. “Such discrepancies create important downstream ripple effects on drug database publishers and other stakeholders who typically rely on these entities for unambiguous standards-based data.” In fact, NCPDP pointed out, the assigning of distinct nonproprietary names of filgrastim and tbo-filgrastim and aflibercept and ziv-aflibercept has resulted in “important inconsistencies within FDA itself.”

Elan Rubinstein, Pharm.D., principal at EB Rubinstein Associates, maintains that as long as stakeholders “include NDC [i.e., National Drug Code] numbers, proprietary name and nonproprietary name in their databases, nonproprietary names can be updated retroactively via an automatic search/change to the FDA-mandated format. However, it will be awkward if some stakeholders implement the FDA-mandated change retroactively while others do not. It may be awkward for stakeholders that do not retroactively change their files but prospectively must use the new FDA-mandated format, because different pre/post drug names complicate drug use trend analysis. There will also be a potentially confusing transition period during which the same product labeled with old and new FDA-mandated format nonproprietary names will be in the channels of distribution, registered differently in drug formularies and physician e-prescribing databases, will be on products inventoried in hospitals, clinics and physician offices, and will be on prescription labels dispensed to patients.”

The Biosimilars Council, a division of the Generic Pharmaceutical Association that launched in April, supports reference biologics and biosimilars using the same INN. “Adverse events and product recalls for small-molecule and biologic drugs already are successfully identified using the national drug code (NDC code), and lot number and company name, and there is no compelling evidence that biosimilars should be handled differently. There is already a precedent for shared names (e.g., erythropoietins, somatropin, interferon), which has not resulted in any known patient safety issues,” said Bertrand C. Liang, M.D., Ph.D., CEO of biosimilar developer Pfenex Inc. and chairman of the Biosimilars Council, in a statement following the release of the documents. He noted that other countries also “safely and effectively” use INNs without suffixes. “Adding a random collection of letters to the product’s nonproprietary name confers no additional safety benefit, and in fact would require the healthcare professional to be armed at all times with a code-breaking reference.”

Indeed, said Academy of Managed Care Pharmacy CEO Edith A. Rosato, “AMCP is concerned that any departure from the currently accepted nonproprietary naming system will create confusion amongst healthcare practitioners and patients, have negative effects on the ability to ensure safe dispensing and tracking, and result in lower market adoption and cost-savings.”

According to Liang, “the legislative intent of the biosimilars approval pathway included in the Patient Protection and Affordable Care Act was to support the development of less expensive but equally effective alternatives to biologic drugs. Yet, today’s proposals could create an unnecessary barrier to the benefits of FDA-determined interchangeability. Patients, prescribers and dispensers of these drugs need to be able to easily identify which drugs bear a relation to one another in order to maximize the potential savings from the biosimilar approval pathway.”

“It will be difficult for pharmacists and physicians to remember and differentiate nonproprietary names of biosimilar(s) and originator brand for a given product, when each nonproprietary name is composed of the same ‘core name’ plus a random/meaningless four-letter suffix,” says Rubinstein. “This naming convention could increase the rate of prescribing and dispensing errors compared to use of a naming convention in which the name is composed of the same ‘core name’ plus a meaningful four-letter suffix,” as the first FDA-approved biosimilar on the U.S. market (see box, p. 8), Sandoz Inc.’s Zarxio, has with filgrastim-sndz.

There are about 80 biologic products on the U.S. market that use the same INN, such as Myozyme and Lumizyme, both with the INN alglucosidase alfa (SPN 5/10, p. 1), and Avonex and Rebif, both with the INN interferon beta-1a (SPN 3/15, p. 1). A query during the Q&A period of a May 20 conference, Biosimilars in the U.S.: Current & Emerging Issues, sponsored by the Alliance for Health Reform and supported by Hospira, Inc. and Amgen Inc., asked whether the FDA would require these products along with biosimilars to have different INNs. Sally Howard, deputy commissioner for policy, planning, legislation, and analysis for the FDA, said that concern had been raised, and that some of “the things we’re struggling with” included whether a naming policy would be applied to biosimilars only or to all biologics, in addition to whether any changes would be done prospectively or retrospectively.

Also responding to the question, Geoff Eich, an executive director at Amgen, said it was “not a fairness or equality issue; it’s an accountability issue.” It would be “no problem,” he maintained, if Amgen reference biologics also were required to add suffixes. Sumant Ramachandra, M.D., Ph.D., a senior vice president and the chief scientific officer at Hospira, said such a requirement “should encompass the field” of products on the market.

However, says the unnamed source, the “immediate impact is on the originator” product, whose company will have a relatively short window of time to comply with the naming change. And besides database changes, companies will need to make sure any contracts that include product names are updated to include the suffix.

According to Lee Rosebush, a partner at BakerHostetler, “Arguably, this could drastically affect those products that are already on the market. As a pharmacist, I can say that many prescribers have specific habits on how they write out prescriptions. By changing names of products that are already currently available, the agency is asking manufacturers to immediately educate pharmacies and prescribers about the specific changes and for prescribers to break these habits. The issue also raises very specific state law-related questions. For example, if a prescriber uses the old name to write a prescription/order, can a pharmacy change the name of the product on the prescription/order? Or will the prescriber have to write a new prescription/order for the patient?”

It will be interesting to see whether the FDA decides to have biosimilars the agency deems interchangeable share the same suffix as that of their reference products, says Rosebush, because “the value of a branding campaign, and the marketing of a drug, is often tied to the advertising and name recognition. It will be interesting to see FDA’s take on whether a suffix is required. By requiring a suffix, FDA could actually help the brands. What happens if a prescriber meant to write for the biosimilar and forgets to include the suffix? Does that result in a sale and/or prescription for the brand product?”

And if the FDA decides to use suffixes based on a drug’s manufacturer, could a change in ownership of either the company or the drug prompt a name change? Yes, says Rubinstein. “If a suffix is based on a drug manufacturer — that is, not a meaningless suffix as proposed in the guidance document — then the suffix will change subsequent to acquisition. This will require the manufacturer to submit to FDA for a changed nonproprietary name and to issue a new product label. The current situation does not require a change in nonproprietary name when one manufacturer acquires another, because the nonproprietary name is the same, but the product’s NDC, which identifies the manufacturer, will typically change,” he tells SPN.

The BPCIA amends the Public Health Service Act, so the guidance is proposed for drugs licensed under the PHS Act only. It also expanded the definition of a “biological product” so it now includes “protein.” But some proteins, including the somatropin class of human growth hormones, have been licensed under the Federal Food, Drug, and Cosmetic (FD&C) Act. The BPCIA has a transition provision for these drugs, and “when these roll over,…they will be a problem,” says the source, who notes that the guidance itself indicates this is a issue. In it, the FDA notes it is “continuing to consider the transition provisions…of the BPCI Act that apply to biological products submitted or approved” under the FD&C Act, “including how those provisions may impact the nonproprietary naming of products to which those provisions apply.” The agency says it “invite[s] comment from all stakeholders” on the issue.

The FDA has issued a handful of proposed guidances on the BPCIA, finalizing three of them earlier this year (SPN 5/15, p. 5). But while various stakeholders have been bemoaning the lack of naming guidance, it appears the FDA may have been working on this guidance for a while: The unidentified source points to the guidance’s docket number, which has a 2013 date. “I think the reg was held up at” the Office of Management and Budget. “Has the FDA been working on this since then? Or is the date a mistake?”

Ultimately, the potential changes and all of their ripple effects are difficult to calculate. “If you’re in a hole, stop digging,” says the source. “But the FDA has employed a backhoe. I can’t see bedrock anywhere in the raison d’être in changing the nonproprietary name.”

Comments on the guidance are due by Oct. 27.

View the guidance at

© 2015 by Atlantic Information Services, Inc. All Rights Reserved.

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