In 2015, FDA issued a number of final guidance documents for biosimilars but many fundamental questions remain unsettled, including the requirements for labeling of biosimilars, interchangeability, and naming. There is much ahead for the US biosimilars pathway in 2016.
2015 was a landmark year for biosimilars. It began with the approval of the first US biosimilar, Sandoz’s Zarxio, in March 2015 under the biosimilars pathway. Zarxio entered the US market in September. Many expected the floodgates to open after Zarxio’s approval but Zarxio remains the only approved US biosimilar to this day, although that is expected to change this year. Seven other biosimilar applications were filed in 2014/2015 and are either being reviewed by FDA or have to be refiled. Most of these applications are to complex biologics. 2016 should provide significant insights into how FDA determines biosimilarity and extrapolation for these complex products.
On January 26, 2016, the World Health Organization (WHO) unveiled the final version of its proposal for a worldwide biosimilar naming convention. The WHO proposes to add a “biologic qualifier” (BQ), which consists of four random consonants and an optional two-digit checksum, as an identifier that follows the nonproprietary name of each biologic and biosimilar product. This proposal resembles FDA’s biosimilar naming proposal, which adds four random consonants as a suffix to nonproprietary names. Industry and healthcare stakeholders have criticized FDA’s proposal to use random suffixes, instead of meaningful—and therefore memorable—ones, due to a greater likelihood of reporting and prescription errors with meaningless names. The WHO proposal, which uses a randomly generated separate identifier, is likely to draw similar criticism.
The Federal Circuit Will Hear Apotex’s Appeal from a Preliminary Injunction Under the BPCIA in Early 2016
In early 2016, the Federal Circuit will hear Apotex’s appeal from a preliminary injunction barring Apotex from selling its proposed Neulasta biosimilar for 180 days after FDA approval. Briefing will be complete on February 12, 2016, and the Federal Circuit agreed to place the case on the oral argument calendar soon thereafter. Apotex had asked for a more expedited schedule but was not able to provide any specific evidence of when its proposed biosimilar product will be approved.
On November 19, 2015, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion, recommending marketing authorization of Samsung Bioepis’s Benepali, the first biosimilar of Enbrel (etanercept), in Europe. Enbrel is a blockbuster treatment for rheumatoid arthritis and a number of other autoimmune conditions associated with elevated levels of tumor necrosis factor alpha (TNF-alpha), a protein that plays an important role in promoting inflammation. The CHMP recommended approval of Benepali for these conditions. In the US, FDA recently accepted Sandoz’s regulatory application for its proposed biosimilar of Enbrel for review. Sandoz is seeking approval for all of Enbrel’s indications. FDA’s review of Sandoz’s proposed biosimilar will provide important information on the requirements for biosimilarity and extrapolation for complex biologic products.
FDA has received comments from more than 170 groups on its proposal for naming biosimilars. Biosimilar makers, insurers and pharmacies largely oppose distinct nonproprietary names (also known as proper names) for biosimilars. By contrast, innovators (including those that develop biosimilars), healthcare providers and patient advocacy groups view them as critical to ensuring patient safety. However, most stakeholders in both camps urged FDA to use meaningful suffixes to distinguish biosimilars from originator products rather than suffixes “devoid of meaning.” FDA proposed to add meaningless suffixes to the nonproprietary names of originator products to address concerns of biosimilar makers that distinct names would discourage adoption of biosimilar products. But biosimilar makers expressed concern that such meaningless suffixes will lead to a variety of errors and ultimately endanger public safety. FDA may now revisit its proposal given the largely uniform preference of innovators and biosimilar makers alike for meaningful and memorable nonproprietary names, such as those that identify the manufacturer of the biologic.
In its draft guidance, FDA proposed distinguishable nonproprietary names for biosimilars to promote the safety of patients receiving biologic medicines and minimize inadvertent substitution of biologics that have not been determined to be interchangeable. FDA did not make a proposal for naming interchangeable biological products. Instead, FDA requested comments on how to name such products in addition to seeking comments on its approach to naming biosimilars. Stakeholders’ comments are now in. Innovator companies (including those that also develop biosimilars), healthcare providers and patient advocacy groups favor distinguishable nonproprietary names for biosimilars. Biosimilar makers, insurers, pharmacies, and the FTC, by contrast, largely fall into a different camp; they argue that distinct names are unnecessary for monitoring biosimilars and will likely bias providers against prescribing them. Notably, the two camps came together on the naming of interchangeable products. Since interchangeable products will likely first be approved as biosimilars, both camps advocated keeping the initial biosimilar name rather than changing it after approval as an interchangeable product. As a result of this unified view, FDA is likely to expand the naming approach it ultimately adopts for biosimilars to interchangeable products.
After the FDA approved the first U.S. biosimilar, Sandoz’s Zarxio (filgrastim-sndz), earlier this year, many predicted that the floodgates would open for biosimilar products. That has not been the case. No other U.S. biosimilar product has been approved. And, as FDA’s recent rejection of Hospira’s EPO biosimilar application suggests, Zarxio’s approval may ultimately provide little guidance for more complex products.
The first biosimilar makers to file regulatory applications with FDA attempted to bypass all or a subset of the patent litigation provisions of the Biologics Price Competition and Innovation Act of 2009 (BPCIA). Apotex, the third biosimilar maker to file an application for approval of a biosimilar product with FDA, chose a different course. Apotex participated in and completed the BPCIA’s pre-suit information exchanges (also known as the “patent dance”) for its proposed biosimilar of Amgen’s Neulasta (pegfilgrastim). As Amgen’s recent lawsuit shows, Apotex followed the patent dance again for its proposed biosimilar of Amgen’s Neupogen (filgrastim).
Sandoz Inc. announced on October 2, 2015 that FDA accepted its regulatory application for a proposed biosimilar of Amgen Inc.’s biologic arthritis drug Enbrel for review. The acceptance comes years after Sandoz attempted to bypass the litigation provisions of the Biologics Price Competition and Innovation Act of 2009 (BPCIA). It remains to be seen whether Sandoz now will follow the BPCIA and provide its regulatory application and other manufacturing information to Amgen since the Federal Circuit has recently held that doing so is optional in Amgen v. Sandoz, another case involving the same parties and the Federal Circuit’s first decision to interpret the BPCIA. Amgen is currently seeking en banc review of this ruling.
The FDA approved label for the first U.S. biosimilar, Sandoz’s Zarxio, has raised concerns. Zarxio was launched on September 3, 2015 with a label that does not state that the product was approved as a biosimilar to Amgen’s Neupogen and that it has not been determined to be interchangeable to Neupogen. Instead, Zarxio’s label is nearly identical to that of Amgen’s Neupogen and does not identify the information provided by Sandoz to FDA to obtain Zarxio’s approval, including information on immunogenicity specific to Zarxio. AbbVie has supplemented its citizen petition urging FDA not to allow biosimilars to be labeled like generic drugs since biosimilars, unlike generic drugs, are not identical to the originator product and requesting distinct labeling for biosimilars. In briefing U.S. senators on September 17, FDA promised to issue guidance on labeling of biosimilars.
On September 18, 2015, Amgen sued Hospira in a fourth lawsuit under the Biologics Price Competition and Innovation Act of 2009 (BPCIA). The lawsuit concerns Hospira’s proposed biosimilar of Amgen’s Epogen (epoetin alfa). Amgen filed the case in Delaware and it has been assigned to Judge Andrews. In addition to its claims for patent infringement, Amgen sued Hospira for failing to comply with the patent litigation provisions of the BPCIA. Hospira’s proposed biosimilar has not been licensed by FDA. FDA also has not announced plans for an advisory committee meeting for Hospira’s product.
The FDA has issued a long-awaited draft guidance document and proposed rule on the nonproprietary names for biosimilar medicines. FDA proposes to give biosimilars a “core name” shared with all related biological products and a four-letter suffix, unique to each product. The four-letter suffix, unlike the placeholder name for the first US biosimilar, Sandoz’s Zarxio (filgrastim-sndz), does not identify the product’s manufacturer. Instead, it is a random collection of four letters, “devoid of meaning.” Patient groups and physicians have applauded FDA’s use of unique suffixes to differentiate biological products but innovator companies prefer meaningful suffixes, such as the one for Zarxio, and biosimilar manufacturers argue for no distinguishing names at all.
In the first skirmishes between biosimilar makers and innovator companies, biosimilar makers attempted to bypass the litigation provisions of the Biologics Price Competition and Innovation Act of 2009 (BPCIA) through the filing of declaratory judgment actions, or by not participating in all or a subset of the BPCIA’s pre-suit information exchanges (also known as the “patent dance”). Apotex, the third biosimilar maker to file an application for approval of a biosimilar product with FDA, chose a different path. As Amgen’s recent lawsuit against Apotex reveals, Apotex is the first biosimilar applicant to participate in and complete the carefully orchestrated pre-suit information exchanges of the BPCIA.
A number of biosimilar makers have turned to inter partes review (IPR) proceedings to challenge innovator patents prior to submitting their biosimilar applications to FDA. IPRs have been attractive to biosimilar makers because in addition to offering procedural and substantive advantages for challenging patents they do not require the filing of a biosimilar application. As a result, they make it possible for biosimilar makers to obtain patent certainty at a time when litigation under the Biologics Price Competition and Innovation Act of 2009 (BPCIA) is premature and, depending on the results of the IPRs, may be avoided entirely. The first such IPRs, however, are yielding mixed results, leaving potential patent disputes for later BPCIA litigation.
Today, FDA published notice of Janssen’s lawsuit against Celltrion and Hospira on March 6, 2015 under the Biologics Price Competition and Innovation Act of 2009 (BPCIA) in the Federal Register. Although Janssen’s lawsuit is not the first action under the BPCIA, today marks the first time the FDA published notice of any BPCIA lawsuit.
The BPCIA created an abbreviated pathway for FDA approval of biological medicinal products that are “biosimilar” to an already FDA-approved product. The FDA recently approved the first U.S. biosimilar – Sandoz’s biosimilar of Amgen’s Neupogen – and is currently reviewing at least four other proposed biosimilars. Many innovators and biosimilars manufacturers are responding to the changing landscape for biologics by developing “biobetters”: new and improved versions of biologic medicinal products. While biobetters require discovery and an original Biologics License Application (BLA) with a full complement of pre-clinical and clinical data for marketing approval, they also offer many advantages. By offering superior and longer-acting medicine, biobetters provide a competitive advantage over biosimilar products. In addition, unlike biosimilars, they generally would be entitled to patent protection and 12 years of non-patent exclusivity under the BPCIA.
A recent FDA guidance document eliminated biosimilar labeling information that FDA previously viewed as “necessary” for physicians to make prescribing decisions, including whether the biologic is biosimilar to or interchangeable with the reference product. The FDA also approved a label for the first approved US biosimilar that omits this information. The FDA’s actions have drawn criticism from associations of physicians who routinely prescribe biologic medicines and the innovator companies that develop them.
On May 13, the FDA released additional draft question-and-answer guidance on the implementation of the BPCIA. The draft document resurrects a number of the questions from FDA’s original 2012 draft guidance that were omitted from last month’s final version of the 2012 document. As a result, FDA’s final answers to important questions from three years ago may not be forthcoming for some time.
A number of biosimilar makers have turned to inter partes review (IPR) proceedings in order to litigate the validity of patents that cover their proposed products in advance of submitting their regulatory applications to FDA. Since IPRs, unlike district court proceedings, do not require a case or controversy, they allow biosimilar applicants to resolve potential patent disputes long prior to being able to litigate these disputes in district court and to potentially avoid the patent dispute resolution procedures of the Biologics Price Competition and Innovation Act (BPCIA) of 2009 entirely.
On March 6, the Food and Drug Administration (FDA) approved the first biosimilar in U.S. history—Sandoz’s biosimilar of Amgen’s blockbuster drug used to prevent infections in cancer patients, Neupogen. Sandoz, a Novartis company, reaped tremendous savings in cost and time by taking advantage of the new biosimilar pathway rather than submitting a full biologics license application (BLA) to the FDA and undertaking all the studies that Amgen had to perform to obtain approval for Neupogen. The extent to which these savings will be passed on to the U.S. health care system as envisioned by the Obama administration, however, is less clear.
On March 25, 2015, FDA denied Amgen’s Citizen Petition asking the FDA to require biosimilar applicants to certify compliance with the information disclosure provisions of the BPCIA before the FDA formally accepts the biosimilar application for review. FDA did not decide whether the disclosure provisions were mandatory, deferring to ongoing litigation on that issue.
Zarxio is the first biosimilar approved under the 351(k) pathway, but it is not the first “biosimilar” to be approved in the U.S. For a small category of follow-on biologics, there is another pathway for marketing approval -- and it is only available for the next five years.
Today the FDA announced approval of the first ever biosimilar in the United States, Sandoz’s Zarxio, a biosimilar of Amgen’s Neupogen (filgrastim) product. Although Sandoz has cleared FDA obstacles, when Zarxio reaches the market depends on the outcome of Amgen’s lawsuit under the BPCIA.
The exclusivity period for biologic drugs has recently become a hot topic in both domestic and foreign policy. At home, the Obama administration’s latest budget proposes reducing the exclusivity period to seven years, down from its current 12. Abroad, the exclusivity period for biologics has developed into a sticking point in negotiations over the Trans-Pacific Partnership.
In the first reported cases on the BPCIA patent provisions, biosimilar makers have sought to bring declaratory judgment actions before engaging in the statutory “patent dance.” The courts have unanimously dismissed these actions as non-justiciable.
Welcome to the Biologics Blog, which will track and analyze developments in intellectual property law related to biologic medical products as well as regulatory and legislative changes. Our impetus for starting the blog is the recent onset of regulatory activity and litigation under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which created a new regulatory and legal framework for biosimilar and interchangeable biologic products.
Nearly five years have passed since the Biologics Price Competition and Innovation Act of 2009 (BPCIA) was signed into law. Although the BPCIA regulatory pathway has been much slower to take shape than its European counterpart, 2015 promises to be a landmark year, with the first biosimilar in U.S. history expected to be approved next month.
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