By Kevin E. Noonan --
The Biologic Price Control and Innovation Act (BPCIA), enacted as part of President Obama's Affordable Care Act (better known as "Obamacare," Public Law 111-148), provided for the first time in the U.S. a path for FDA approval of biosimilar drugs, i.e., "generic" versions of biologic drugs that, unlike generic versions of conventional small molecule drugs are not identical but similar. Congress did not, however, prescribe the standards for establishing biosimilarity or other aspects of the biosimilar pathway, leaving the details up to the FDA. As part of fulfilling its mandate under the BPCIA, the FDA has issued a series of Guidances (both in draft and final form) with respect to the procedural and scientific protocols to be followed in filing and pursuing a biosimilar drug application (see "FDA Releases 'Final' Guidances for Industry regarding the Biosimilar Approval Pathway"). On Friday, the FDA issued its latest Guidance, which has to do with labeling of biosimilar drugs. Far from being merely a technical aspect of the biosimilar program, this Guidance has been subject to pressures from both the innovator biologic drug makers and companies pursuing (or planning to pursue) their own biosimilar drugs. These pressures have everything to do with the hoped-for acceptance of these drugs (particularly by the U.S. government, the biggest payor for biologic drugs) and fears by innovator biologic drug companies that their drugs might be mistaken for a biosimilar version (especially in the event that a biosimilar is associated with an adverse event).
The Guidance (which is but a draft Guidance for now) on its face is being distributed "for comment only" and in this way reflects the manner in which the FDA has approached its task of implementing the Act, by soliciting public and industry feedback by issuing draft Guidances and holding hearings and other meetings. In a "black box" at the beginning of the document it states:
This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.
There are eight sections, providing the Background, General Principles, Specific Recommendations, FDA-approved Patient Labeling, Revised Biosimilar Product Labeling, instructions on how to submit initial and revised labeling, and a short section on Interchangeable Biological Products that does not provide labeling recommendations for interchangeable products (consistent with the agency's refusal to provide Guidance on obtaining approval for interchangeable versions of biologic drugs). In the short Background the agency explains the context of the biosimilar provisions of the Act and then moves immediately to the General Principles. There the FDA notes that the biosimilars pathway is provided "to demonstrate biosimilarity between the proposed [biosimilar] product and the reference product, not to independently establish safety and effectiveness of the proposed [biosimilar] product." Accordingly, the information on the biosimilar label should be the "relevant data and information from the reference product labeling, with appropriate product-specific modifications." Indeed, "[i]nformation and data from a clinical study of a proposed biosimilar product should be described in its labeling only when necessary to inform safe and effective use by a health care practitioner" and should not include "a description of these data," on the grounds that any clinical study undertaken by the biosimilar applicant should be aimed at establishing biosimilarity (defined as there being no clinically meaningful differenced between the biosimilar product and the reference product) and not at assessing the safety and efficacy of the biosimilar per se. The Guidance also recites several other labeling rules not limited to the biosimilar context that a biosimilar label is required to follow (see, 21 CFR 201.56(c)(1), 201.56(d) and 201.57, and 21 CFR 201.57(c)(9)(i) through (iii)).
With regard to the Specific Recommendations for biosimilar products, the Guidance accommodates circumstances where the biosimilar product label differs from the reference product label (for example, depending on whether the biosimilar applicant is seeking approval for all or just a subset of indications for which the reference product has been approved). The Guidance reaches the crux of the matter with regard to product identification; an earlier version of the agency's thinking in this regard was disclosed previously. The agency recommends using the biosimilar product name "[i]n sections where the information described is specific to the biosimilar product" and "[f]or directive statements and recommendations for preventing, monitoring, managing, or mitigating risks." The reference product name should be used "[w]hen clinical studies or data derived from studies with the reference product are described in biosimilar product labeling," particularly with regard to clinical studies and adverse reactions. The "core" name (which is the nonproprietary name without the source-specific suffix) should be used when the property or risk applies to both the reference and biosimilar products (exemplified in the Guidance as "BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS (Postmarketing Experience)" which would reflect the commonality of these properties for both products. The FDA also apprehends situations where "[t]here may be text appropriately based on the reference product labeling where more than one of these product identification approaches should be used to accurately convey information." For instances where a biosimilar has sought (and been approved for) fewer than all the indications approved for the reference product, information relating to these indications should not be included unless it is necessary for safety or efficacy (whilst ensuring that it is clear that the biosimilar is not approved for such uses).
The Guidance then recites the recommendation for specific language regarding a biosimilar:
[BIOSIMILAR PRODUCT'S PROPRIETARY NAME (biosimilar product's proper name)] is biosimilar* to [REFERENCE PRODUCT'S PROPRIETARY NAME (reference product's proper name)] for the indications listed.
The INDICATIONS AND USAGE section of the label "should be specific to the approved indications for the biosimilar product and should be consistent with language previously approved for the reference product for those indications" including text from the reference product related to Limitations of Use. The FDA also recommends specific language related to immunogenicity:
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to [reference product's proper name] in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
Not surprisingly, the agency recommends that Patient Labeling follow the reference product except when differences are necessary to properly describe the biosimilar product.
The agency also recognizes that changes may arise during the life cycle of a biosimilar product and provides mechanisms for updating safety information, particularly when "new information" relating to use of the product under "more widely or [] diverse conditions." Specifically, "[a]s with any biological product, a biosimilar product application holder must promptly review all adverse drug experience information obtained or otherwise received from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological studies/ postmarketing adverse event surveillance, reports in the scientific literature, and unpublished scientific papers; and the biosimilar product application holder," citing 21 CFR 600.80. And if any information is found to be inaccurate, prompt correction is mandated by the statute (see, 21 CFR 601.12). The Guidance also provides for post-approval licensure for additional indications for which the reference product has been approved.
How such labeling information should be submitted is set out as requiring:
• A clean version of reference product labeling that was used to develop the biosimilar product labeling
• A tracked changes and annotated version of proposed biosimilar product labeling explaining the differences from the reference product labeling
• A clean version of the proposed biosimilar product labeling
Finally, the Guidance indicates that, while "FDA continues to consider the types of data and information that would support a demonstration that a biological product is interchangeable with a reference product" that Guidance will not be found here.
As noted above the FDA is soliciting comments; as the face of the Guidance states, "[c]omments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance," with electronic copies to be sent to http://www.regulations.gov and questions to Sandra Benton at 301-796-1042 or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.
Top Stories of 2014: #10 to #7
By Donald Zuhn --
10. While FDA Accepts First Biosimilar Application, Some Biosimilar Applicants Try to Bypass BPCIA
In July, Sandoz announced that the U.S. Food and Drug Administration had accepted its application to market a version of the protein filgrastim. The reference product is Amgen's NEUPOGEN®. Sandoz markets a biosimilar filgrastim outside the U.S. under the brand name ZARZIO®. Interestingly, in October, Amgen announced the results of a Phase III clinical trial of its own biosimilar drug (designated ABP 501) for moderate-to-sever plaque psoriasis conducted in comparison with adalimumab (sold by AbbVie as Humira®). Amgen and Sandoz were both involved in a BPCIA dispute that was resolved by the Federal Circuit in December. In what some perceived as an attempt to sidestep the requirements of the BPCIA, Sandoz filed a declaratory judgment action against Amgen and Roche related to its etanercept biosimilar drug product, which it developed to compete with Amgen's Enbrel® TNF inhibitor. In Sandoz v. Amgen, the Federal Circuit affirmed the District Court's dismissal of Sandoz's suit because "Sandoz did not allege an injury of sufficient immediacy and reality to create subject matter jurisdiction." In other biosimilar developments, the FDA issued a "Guidance for Industry" in August entitled "Reference Product Exclusivity for Biological Products file under Section 351(a) of the PHS Act." The Guidance provides some grounds for determining the term of market exclusivity under the BPCIA (12 years; Sec. 351(k)(7), codified at 42 U.S.C. 55 262(k)).
For information regarding this and other related topics, please see:
• "Celltrion Healthcare Co. v. Kennedy Trust for Rhematology Research (S.D.N.Y. 2014); Hospira Inc. v. Janssen Biotech Inc. (S.D.N.Y. 2014)," December 11, 2014
• "Sandoz Inc. v. Amgen Inc. (Fed. Cir. 2014)," December 9, 2014
• "Amgen Poised to Enter Biosimilars Market," October 8, 2014
• "FDA Releases Another Prospective Guidance," August 13, 2014
• "Finally, A Biosimilar Application Has Been Accepted By The FDA ," July 28, 2014
• "FDA Releases Draft Guidance on Biosimilars," May 14, 2014
• "Indiana Governor Signs Biosimilar Substitution Bill," April 10, 2014
9. Congress and Tech Sector Wage Battle Against Patent Trolls
Despite having passed patent reform legislation -- the Leahy-Smith America Invents Act -- in September 2011, many in the patent community expected Congress to pass another piece of patent reform legislation in 2014 -- this time addressing patent litigation and the problem of so-called patent trolls. However, after taking up and tabling legislation in March and April, Senator Patrick Leahy (D-VT), Chairman of the Senate Committee on the Judiciary, announced that he was taking the Patent Transparency and Improvements Act of 2013 (S. 1720) off the Committee's agenda because of a lack of "sufficient support behind any comprehensive deal." Meanwhile, the tech sector continued to lobby for patent litigation reform. Congress may take up patent reform again this year.
For information regarding this and other related topics, please see:
• "More Misinformation Regarding the Patent System and Non-Practicing Entities," December 18, 2014
• "Patent Litigation Reform -- Will the Outcome of the Mid-Term Elections Matter, and Is Reform Still Necessary?" October 30, 2014
• "Teva v. Sandoz -- Is Deferential Review a Boon for Patent Trolls?" October 14, 2014
• "House Tries One More Time: Targeting Rogue and Opaque Letters Act of 2014 ("TROL Act")," July 17, 2014
• "Patent Reform Legislation Off The Table -- For Now," May 21, 2014
• "Senate Judiciary Committee Tables Patent Reform, Again," April 3, 2014
• "Stopping Bad Legislation -- The Innovation Alliance Speaks Out," April 2, 2014
• "Stopping Bad Patents -- Senator Schumer Takes on the "Patent Trolls"," April 1, 2014
• "New York Times Op-Ed Argues Law Takes Misguided Approach to Software Patents," March 30, 2014
• "Senate Judiciary Committee Takes Up, Then Tables, Patent Reform," March 27, 2014
• "A Rebuttal to The Economist's "Stalking Trolls"," March 13, 2014
• "Senate Legislation Update -- The Commerce Committee Gets in the Act," March 5, 2014
8. Courts and PTAB Deal with Fallout of Alice Corp. v. CLS Bank
In June, the Supreme Court issued its opinion Alice Corp. v. CLS Bank International, affirming the Federal Circuit's per curiam opinion in CLS Bank International v. Alice Corp. (stay tuned for more on that decision as we move closer to the top three stories of 2014). However, the impact of the Supreme Court's Alice Corp. opinion on Federal Circuit and Patent Trial and Appeal Board decisions made it to #8 on the list. Patent Docs covered nine such decisions during the second half of 2014, and in only one case (DDR Holdings, LLC) did the Federal Circuit conclude that computer-implemented claims survive a § 101 challenge. Readers can look for more discussion of this top story, as well as the Supreme Court's Alice Corp. decision, during our live webinar on the "Top Patent Law Stories of 2014" on January 20, 2015.
For information regarding this and other related topics, please see:
• "DDR Holdings, LLC v. Hotels.com, L.P. (Fed. Cir. 2014)," December 8, 2014
• "Ultramercial Inc. v. Hulu LLC (Fed. Cir. 2014)," November 16, 2014
• "Ultramercial Inc. v. Hulu LLC -- Party Briefs," November 6, 2014
• "Cambridge Assoc., LLC v. Capital Dynamics (PTAB 2014); PNC Bank v. Secure Axcess, LLC (PTAB 2014)," October 16, 2014
• "U.S. Bancorp v. Solutran, Inc. (PTAB 2014)," September 10, 2014
• "Planet Bingo, LLC v. VKGS LLC (Fed. Cir. 2014)," August 27, 2014
• "I/P Engine, Inc. v. AOL Inc. (Fed. Cir. 2014)," August 18, 2014
• "Stewart Title Guaranty Co. v. Segin Software, LLC (PTAB 2014)," July 23, 2014
• "Digitech Image Technologies, LLC v. Electronics For Imaging, Inc. (Fed. Cir. 2014)," July 14, 2014
• "Cyberfone Systems, LLC v. CNN Interactive Group, Inc. (Fed. Cir. 2014)," March 3, 2014
• "SmartGene, Inc. v. Advanced Biological Laboratories, SA (Fed. Cir. 2014)," January 29, 2014
7. Supreme Court Addresses Fee Shifting Determinations in Exceptional Cases
In April, the Supreme Court issued opinions in Octane Fitness, LLC v. ICON Health & Fitness, Inc. and Highmark Inc. v. Allcare Health Mgmt. Sys., Inc. The issue in both cases centered on the attorney fee-shifting provision of 35 U.S.C. § 285. In Octane Fitness, a mostly unanimous court held that "an 'exceptional' case is simply one that stands out from others with respect to the substantive strength of a party's litigating position (considering both the governing law and the facts of the case) or the unreasonable manner in which the case was litigated," the Court leaving the determination of whether a case is "exceptional" to the discretion of the District Court judge. In Highmark, the Supreme Court determined that "an appellate court should apply an abuse-of-discretion standard in reviewing all aspects of a district court's §285 determination," even though "questions of law may in some cases be relevant to the §285 inquiry." The Supreme Court's decisions make it easier for a trial court to shift fees to the non-prevailing party if it believes that the litigation was brought or conducted in an abusive manner, and also make it more difficult for an appellate court to overturn such a determination.
For information regarding this and other related topics, please see:
• ""Standing Out" -- A Closer Look at the "Exceptional Case" Standard Articulated in Octane Fitness," April 29, 2014
• "Patent Trolls Beware -- Supreme Court Issues Decisions in Octane Fitness and Highmark," April 29, 2014
• "Oral Arguments in the Supreme Court Octane Fitness, LLC v. ICON Health & Fitness, Inc. Case," February 27, 2014
• "Supreme Court to Hear Oral Arguments in Attorney Fee Shifting Cases," February 25, 2014
• "Supreme Court Preview -- Highmark Inc. v. Allcare Health Mgmt. Sys., Inc.," February 19, 2014
• "Supreme Court Preview -- Octane Fitness, LLC v. ICON Health & Fitness, Inc.," February 13, 2014
Posted at 11:59 PM in Biosimilars, Federal Circuit, Food and Drug Administration, Media Commentary, Patent Legislation, Patent Trial and Appeal Board, Patentable Subject Matter, Supreme Court | Permalink | Comments (0)