Life Science Compliance Update

August 28, 2015

Be Careful What You Wish For? FDA’s Biosimilars Naming Guidance Proposes New Identifiers For All Biologic Products

Name tag

Yesterday, the Food and Drug Administration (FDA) released much anticipated guidance on how they plan to address nonproprietary naming of biologics and biosimilars. In it, FDA proposed that all biologics—both reference products and biosimilars—will share a core drug substance name and also a new “FDA-designated suffix” that is unique for each product. While brand-biologic manufacturers pressed FDA to ensure biosimilars carry unique names, the agency’s proposal in fact places a large burden on these manufacturers and prescribers to adopt the new naming model. 

In March, FDA approved the first biosimilar product, Zarxio—Sandoz Inc.’s copy of Neupogen (filgrastim). At the time, FDA referred to Sandoz’s biosimilar as “filgratism-sndz,” which seemed to suggest that FDA was headed towards a unique-naming scheme for biosimilars. However, it turns out the agency only partially showed their hand. Their draft guidance reveals the agency wants all biologics, including the reference product, to be renamed under a four-letter suffix scheme.

Janet Woodcock, the Director of the Center for Drug Evaluation and Research (CDER) and Karen Midthun, Director of the Center for Biologics Evaluation and Research (CBER) published an overview of their agency’s plan and how how the naming would work. “This suffix would be composed of four lowercase letters, and not carry any meaning,” they write. “For example, the nonproprietary name of a reference product could be replicamab-cznm, and a biosimilar to that product could be replicamab-hixf.”

In the time leading up to this guidance, most of the commentary surrounding the “naming” issue focused primarily on the biosimilar product. In broad terms, the biosimilar industry and insurers argued that FDA should assign a biosimilar the same nonproprietary name as the reference product on which it was based in order to facilitate substitution by providers and pharmacists. Brand manufacturers argued that because biologics are inherently complex and impossible to replicate in the way small-compound drugs can, biosimilars should carry different nonproprietary names. Specialists who often prescribe biologics also called for unique naming for biosimilar products, arguing this was necessary to clarify that biosimilars are not identical to reference products and may not be approved for all the same conditions as the reference, as well as to prevent confusion regarding adverse event reporting.

Interestingly, neither side seemed to be lobbying for a change in the naming scheme for all biologics, including reference products. Gillian Woollett, Senior Vice President at Avalere Health, notes that the immediate impact of the proposed guidance and accompanying regulation on the originator products is actually much greater than the impact on biosimilars. It is unclear how manufacturers will retroactively change the names for their products, and the implementation of FDA’s proposal could result in substantial disruption along the supply chain as data systems have to accommodate multiple names for the same product, some concurrent. This has never happened before. We expect this issue to feature prominently in the comments FDA receives.

“[W]e must also consider what we need to do to address previously approved biological products that have nonproprietary names without a suffix,” the FDA Directors acknowledged. “Applying the naming convention to these products would encourage routine use of designated suffixes in ordering, prescribing, dispensing, and recordkeeping practices and avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway.” FDA is seeking comment on the best approach to implement this naming convention for previously licensed products.

FDA is also issuing a proposed rule to designate nonproprietary names that contain a suffix for six previously licensed biological products. Each of the six products is either a reference product for an approved or publicly disclosed biosimilar product application or a biological product that is either biosimilar to or related to one of these reference products. For example, Johnson & Johnson’s arthritis treatment Remicade (infliximib) would be have to be changed to infliximab-hjmt, according to the proposed rule.

Woodcock and Midthun note that FDA’s aim with the proposed naming convention is to address two issues, both of which were put forth by the brand industry as reasons to apply unique names to biosimilars. 

First, FDA wants to help prevent inadvertent substitution of biological products that are not determined to be “interchangeable” by the FDA. The agency has not yet issued guidance on how they will determine whether biosimilar products rise to the level of “interchangeability,” but FDA is getting a jump start on the naming issue. The agency is soliciting feedback about whether the nonproprietary name for interchangeable products should include a distinct suffix, or should share the same suffix as its reference product. The FDA will presumably also need to address currently marketed biologic products that share nonproprietary names as these may also be in danger of now being presumed to  be interchangeable if nonproprietary names are to become the basis of interchangeability.

Second, FDA is seeking to facilitate “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.” Peter Pitts, President at the Center for Medicine in the Public Interest agreed that FDA’s proposal is an important one. “FDA has come out in favor of patient safety with the ability to track adverse events back to the manufacturer,” he noted.

View FDA’s draft guidance that explains FDA’s proposal on nonproprietary naming of biologicals (comments close in 60 days). View FDA’s proposed rule for renaming existing biologics (comments close in 75 days).

June 04, 2015

Biosimilars: Abbvie Finds Fault with Zarxio Label, Submits Citizen Petition

On June 2, AbbVie, Inc. submitted a citizen petition requesting that FDA require the approved prescription drug labeling for biological products licensed under the Public Health Service Act (PHSA) include:

(1) A clear statement that the product is a biosimilar, that the biosimilar is licensed for fewer than all the reference product's conditions of use, and that the biosimilar's licensed conditions of use were based on extrapolation;

(2) A clear statement that FDA has not determined that the biosimilar product is interchangeable with the reference product; and

(3) A concise description of the pertinent data developed to support licensure of the biosimilar, along with information adequate to enable prescribers to distinguish data derived from studies of the biosimilar from data derived from studies of the reference product.

AbbVie contends this information in biosimilar labeling is necessary to "enable rational and informed prescribing decision regarding these complex products, to avoid potentially unsafe substitution of biosimilars and reference products, and to combat widespread misconceptions among prescribes about biosimilars and their relationship to reference products." The citizen petition further asserts without this information biosimilar labeling will not reflect licensure provisions in the Biologics Price Competition and Innovation Act of 2009 (BPCIA) and will be "materially misleading in violation" of Food, Drug, and Cosmetic Act (FDCA) and FDA regulations. AbbVie also alleges a violation of the Administrative Procedure Act (APA).


The BPCIA created a two-tiered abbreviated licensure pathway for follow-on biological products. It can be licensed under BPCIA if it is "biosimilar" to a "reference product" as defined in the PHSA. Alternatively, a biosimilar can be deemed "interchangeable" with a reference product if certain heightened showings required by the PHSA have been made. As noted in the petition, on March 6, 2015, FDA approved the first biosimilar product in the United States (Zarxio®). AbbVie claims that the labeling for this product mimics the approved labeling for Neupogen (which has not been found to be interchangeable with Zarxio), "which suggests that FDA has decided to apply the 'same labeling' requirement found in FDCA … for small-molecule generic drugs to biosimilars licensed under … the PHSA." AbbVie also argues public materials from FDA's review of Zarxio confirms that the agency followed this "same labeling" approach.


AbbVie argues it would be legally unsound for FDA to adopt this approach to biosimilars for three reasons. First, the company asserts this is inconsistent with BPCIA which includes no "same labeling" requirement and "recognizes that biosimilars are different from their reference products." Second, this labeling approach to biosimilars would result in misconceptions among prescribers regarding biosimilars. Third, FDA did not follow APA requirements to explain its decision to abandon the approach outlined in its Draft Scientific Guidance, which stated the extent of labeling for biosimilars.

The petition describes the characterizing feature of the BPCIA pathway as one that deems biosimilars to be unique from their referents. AbbVie notes that Congress established distinct approval pathway for biosimilars, and that pathway includes "no analogue to the same labeling requirement that exists for small-molecule generic drugs under the ANDA provisions of the FDCA." This, AbbVie contends, distinguishes the BPCIA from the FDCA's ANDA provisions. By using the same labeling requirements for both ANDA products and biosimilars, it lacks legal foundation and "would conflict with the novel licensing scheme established by the BPCIA."

Additionally, AbbVie's petition argues, the "same labeling" requirement to biosimilars leads to misleading labeling in violation of the FDCA and FDA regulations. As described by a number of groups in a letter to FDA leadership, "the level of education that still needs to take place surrounding biosimilars, some physicians may mistakenly view that an identical label implies that a biosimilar is interchangeable with the reference product and has approval for all of the same indications—which we know may not be the case for many biosimilars." This runs contrary to stated goals in FDA regulations, that drug labeling should affirmatively present safety and effectiveness information needed for informed prescribing or rebut misconceptions.

FDA regulations further state that "the basis for approval of the drug product, including the extent of the product's benefits," should be included in labeling to "provide practitioners with more accurate and specific information about a drug's efficacy that could help them to make informed prescribing decisions." The petition infers from this that FDA regulations thus provide the basis for a drug's approval to be disclosed in its approved physician labeling. Omissions in Zarxio labels result in "materially misleading biosimilar labeling," running starkly in contrast to this stated policy.

Interestingly, the petition also cites non-American jurisdictions which require biosimilar labeling to include information at issue in AbbVie's petition. For example, guidance from Health Canada states that unlike "generic pharmaceutical drugs, the sponsor of a [biosimilar] will not be able to utilize the [labeling] of the reference biologic drug in its entirety as that of its own product." Labeling for the biosimilar will include statements indicating the product is a biosimilar, information regarding the indications approved for use, and data on which the decision for market approval was made. In the petition, AbbVie asserts that similar information "should be provided to prescribers in the United States" because physicians "need and want to know whether a product is a biosimilar, the scope of its approval, and whether the approval was based on extrapolation." AbbVie points out that FDA proposed to require labeling statements like this in 2012 in a guidance stating that biosimilar labeling "should include all the information necessary for a health professional to make prescribing decisions."

The petition continues, arguing that prescribers need to know whether a biosimilar is, in fact, interchangeable with the reference product. Without this information, prescribers may not be able to tell "whether the biosimilar is a potential substitute for the reference product". Such an omission "misleadingly suggests that the biosimilar could be substituted for its referent, just like a generic drug, which increases the risk of inappropriate product switching." Furthermore, AbbVie contends that prescribers need biosimilar-specific data and also need to know whether data discussed in labeling are from the biosimilar itself, or from the reference product, to avoid omitting important safety and efficacy information.


AbbVie's citizen petition challenges important considerations surrounding the labeling of biosimilars. The labeling protocol the FDA used was the same one they typically use for generic drugs.  

Another problem with the labeling, this one for biosimilar manufacturers in the Zarxio label is that none of the clinical or analytical data that supported the finding of bio similarity to the reference product is included in the label, which will put biosimilars at a disadvantage when they go to detail the product to physicians, pharmacists and payers. Much of what they would talk about for a branded drug will be considered off label promotion.

The company believes appropriate labeling on these drugs are critical to informed prescribing and avoiding potentially unsafe substitution of biosimiliars and reference products. As pointed out in the Wall Street Journal, researchers expect biosimilars to sell at discounts to their original reference drugs of between 20% and 30%. If that proves accurate, first movers on biosimilars, such as Pfizer and Novartis, are poised to benefit. This would come at the expense of those companies that have blockbuster drugs facing loss of exclusivity but have not invested in biosimilars, such as AbbVie and Roche. Thus, we can expect these fights to continue as more biosimilars are on their way. We will continue to monitor this issue closely.



March 24, 2015

District Court Denies Amgen’s Motion for Preliminary Injunction to Prevent Marketing of Sandoz’s Biosimilar Zarxio

Biosimilar pic

The first U.S. biosimilar is one step closer to entering the marketplace. Last week, U.S. District Judge Richard Seeborg of the Northern District of California denied Amgen's request for a preliminary injunction to block Sandoz from selling its version of Neupogen. The Food and Drug Administration approved Sandoz’s biosimilar application for “Zarxio” earlier this month.

Amgen had argued that Sandoz should have provided its Biologic License Application and manufacturing plans within 20 days after the FDA accepted the application, in accordance with the "patent dance" procedure laid out in the biosimilar statute. Amgen also argued that Sandoz should have provided six-months notice of its plans to market an FDA approved biosimilar. 

Judge Seeborg’s concluding remarks sums up his view:

“As the twelve-year exclusivity period for Neupogen long ago expired, there exists no substantive bar to market entry for Sandoz’s biosimilar filgrastim—and, consequently, no basis on which Amgen is entitled to injunctive relief or other remedies for disadvantages it may suffer due to market competition from Sandoz.”


Sandoz’s biosimilar of Neupogen is the first application to be approved using the new biosimilar pathway created by the Biologics Price Competition and Innovation Act (BPCIA). This path allowed Sandoz to reduce the costs associated with bringing its drug to market if they could show their Neupogen-copy was “biosimilar” to the already approved product.  Sandoz announced last July that the FDA had accepted its biosimiar application.

Under the 351(k) pathway, so-named because of the statute provision, the law also lays out a detailed “patent dance." The provisions in the law coordinate how the reference product manufacturer and the potential biosimilar manufacturer would handle a web of complicated legal issues associated with the biosimilar, in effect, copying the reference product.

The statute states that “20 days after…the application has been accepted for review, the subsection (k) applicant…shall provide to the reference product sponsor a copy of the application submitted to the Secretary under subsection (k).” Thus, after approval, Sandoz had 20 days to provide Amgen with a copy of its filing, as well as other manufacturing details. Amgen would then have 60 days to return a list of patents it could claim that Amgen had infringed, and those it would be willing to license. After a few rounds of information exchanges, the statute indicates that the companies must begin “good faith negotiations” to identify the patents to be tested in lawsuits.

No Patent Dance

Amgen alleged that Sandoz never even started the patent resolution procedures. According to Amgen, Sandoz received notice that FDA accepted the company’s 351(k) application, but refused to engage in the disclosure deadline that should have happened within 20 days of that acceptance. On October 24, 2014, Amgen filed a complaint in the District Court for the Northern District of California alleging that Sandoz unlawfully refused to engage in the "patent dance," and sought injunctive relief. 

Furthermore,  Sandoz notified Amgen in July 2014 that it would begin commercially marketing its biosimilar likely by the second quarter of 2015. Amgen argued that Sandoz would instead have to delay its marketing until 180-days after FDA eventually approved the product. Amgen relied on the BCPIA provision stating: "The subsection (k) applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k)." Amgen focused on the "licensed" language to argue that Sandoz's notice must come after FDA approved the product--thus Sandoz would have to wait 180-days after March 6, 2015, so at least until September 6, to finally market Zarxio. 

District Court Denies Injunction

Sandoz countered Amgen's preliminary injunction, arguing that the BCPIA patent dance outlined in the statute was not mandatory, but optional. Sandoz also argued that biosimilar manufacturers should not have to wait for FDA to approve their product before giving notice to the reference product manufacturer. 

Judge Seeborg agreed, focusing on the statute's language (including dissecting the use of the words "shall" and "may"). "Congress intended merely to encourage use of the statute's dispute resolution process in favor of litigation, where practicable, with the carrot of a safe harbor for applicants who otherwise would remain vulnerable to suit," Seeborg wrote in his March 19th opinion. "The statute contains no stick to force compliance in all instances, and Amgen does not identify any basis to impute one."

Compliance with the patent dance “allows an applicant to enjoy a temporary safe harbor from litigation and, potentially, to resolve or narrow patent disputes outside court proceedings," he noted. The statute is only “required,” when “the parties elect to take advantage of their benefits.” 

In siding with Sandoz on the 180-day provision argument, Judge Seeborg seemed convinced that Amgen had already enjoyed enough exclusivity and didn't need an extra six months. "Because the FDA cannot license a biosimilar until twelve years after approval of a reference product, Amgen’s reading would tack an unconditional extra six months of market exclusivity onto the twelve years reference product sponsors already enjoy," he noted.  "Had Congress intended to make the exclusivity period twelve and one-half years, it could not have chosen a more convoluted method of doing so. Moreover, Congress presumably could have been far more explicit had it intended for infringement suits to commence only once a biosimilar receives FDA approval."

He concluded: "It was, therefore, not wrongful for Sandoz to give Amgen its 180 days’ notice prior to first commercial July 2014, in advance of receiving FDA approval."

Download Judge Seeborg's BCPIA Opinion

FDA Law Blog, which has covered the patent provisions in the BCPIA in several comprehensive articles, states that the decision could have wide-ranging implications: “the victory scored by Sandoz, if upheld, could forever alter the biosimilars landscape in the U.S. by affirming that the complex patent resolution procedures under the BPCIA (which some might say are a disincentive to seeking approval of a highly similar biosimilar or interchangeable biosimilar biological product) are not the only game in town.”


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