INNsight article by Alan Klein, April 2015

Hope is on the horizon for the generic drug industry since the U.S. Food and Drug Administration’s (FDA) recent approval of the first biosimilar product in America—likely to be called Zarxio when sold—additional biosimilar applications in the agency’s pipeline, and more on the way. The administrative log-jam delaying the development of this new market in the United States is now relatively free of obstacles that have prevented these medicines from reaching patients and their health insurance carriers. With the yearly treatment cost for individual patients running in the thousands of dollars—in some instances upwards of $100,000—physicians and consumer groups have clamored for a quicker pathway for biosimilar approvals. Congress, through its Biologics Price Competition and Innovation Act of 2009 (BPCIA), and the FDA have been listening—and responding.

FDA Approves Sandoz’s Neupogen Biosimilar

On March 6, following the unanimous vote of its Oncology Drugs Advisory Committee, the FDA approved the United States’ first biosimilar. Zarxio, a generic equivalent of Amgen’s Neupogen, which is indicated for patients undergoing chemotherapy or with severe neutropenia, an immune system disorder that hinders the production of white blood cells. While the agency completes a draft guidance on the naming of biologic drugs, it has assigned Zarxio a “placeholder non-proprietary name” of “filgrastim-sndz.”

Other biosimilar applications await FDA approval, including Celltrion’s August 2014 application for its biosimilar of Remicade; Hospira’s December 2014 application for its biosimilar of Epogen; and Apotex’s December 2014 and February 2015 applications for its biosimilars of the biologics Neulasta and Neupogen. Many more biosimilar applications are anticipated, along with applications for “interchangeable” biologics. Introduction of competing biosimilar versions of complex biologics used to treat illnesses, such as cancer, hemophilia and rheumatoid arthritis, could save consumers, health insurance carriers and government-sponsored programs upwards of $44 billion over a 10-year period.

Remaining Concerns for the Biosimilars and Biologics Industry

With a better-defined pathway for product sponsors through a series of FDA guidance documents on the development and approval of biosimilar medicines, concerns continue on several fronts for the industry, physicians, pharmacists and others.

The Naming of Biosimilar Drugs: Perhaps the foremost issue is the naming of these medicines. Many have advocated for a uniform, non-proprietary name for biosimilars and their brand name, or reference-listed products. They contend that using the same name for both drugs would assuage concerns among physicians, patients and pharmacists and lead to the appropriate substitution of biosimilars for their branded counterparts. In America, the Generic Pharmaceutical Association (GPhA) has long lobbied the FDA to adopt the International Nonproprietary Name (INN) system in use elsewhere to avoid confusion and promote greater physician and patient acceptability.

State Legislation Regarding Biosimilars Prescription and Use: Biosimilar sponsors and their allies have sought to defeat state legislation—sponsored in large part by brand biologics companies—that would condition the prescription and dispensing of biosimilars in lieu of branded biologics on mandatory disclosures by physicians and pharmacists to one another and to patients. Such efforts, they contend, are purposed to discourage the prescription and use of biosimilars. Thus far, many such efforts have been defeated at the state level, but they are continuing and in a few states have been enacted into law.

Scientific Data Necessary for the FDA’s Approval of Biosimilars: More than five years after the BPCIA was enacted, it is unknown precisely what scientific data the FDA will require biosimilar sponsors to marshal and present for marketing approval. For Sandoz’s Zarxio, the FDA relied upon evidence that included a structural and functional comparison of its filgrastim product with Neupogen, and animal and human study results and other clinical data comparing the drug to its branded competitor.

If enacted, a bill recently introduced into the House of Representatives would require the FDA to use data from biosimilar approvals by foreign regulatory agencies to speed up the U.S. approval process. The FDA’s review of each biosimilar application primarily is to determine the risk of immunogenicity of the new product (the risk of an adverse immune response in the patient) in relation to its referenced biologic. The use of foreign-generated data potentially could greatly accelerate domestic biosimilar approvals. In approving Sandoz’s filgrastim biosimilar, the FDA appeared to take comfort in the fact that Zarxio had been sold for years in Europe and other developed economies (7.5 million days of patient exposure, the company told the agency’s investigative committee).

Another bill introduced this session in the House of Representatives, if enacted, would create a mechanism for addressing the need for either additional legislation or FDA regulation specifying criteria for the approval of biosimilars, including the kinds and type of evidence necessary to demonstrate bioequivalency between the biosimilar and branded product.

Patent Battles over Biosimilars

“Patent Dance”: The BPCIA provides an informal information exchange process to the biologic sponsor and biosimilar applicant—popularly known as a “patent dance.” The purpose of this process is to narrow, and perhaps eliminate, patent infringement litigation. Under the statute, the applicant furnishes its biologics license application (BLA) to the reference product sponsor under conditions of confidentiality, and the parties thereafter determine which, if any, patents are at issue. If the biosimilar applicant refuses to engage in this procedure, the biologic sponsor may immediately bring a lawsuit claiming infringement of its patents.

With regard to Zarxio, Sandoz originally agreed to provide its BLA to Amgen, but then declined to do so over confidentiality concerns. Exercising its rights under the BPCIA, Amgen then sued Sandoz for patent infringement, asserting that Sandoz was required to participate in the statute’s patent information exchange procedure. Sandoz disagreed and contended that its participation in these procedures was optional, not mandatory.

Sandoz Prevails, Amgen Appeals: On March 19, 2015, a California federal judge ruled that the patent dance procedures of the BPCIA are optional for the biosimilar applicant. It denied Amgen’s request for an injunction to prevent Sandoz’s launch of its filgrastim product. Amgen appealed this decision to the United States Court of Appeals for the Federal Circuit, and the parties have requested an expedited briefing schedule. In the interim, Sandoz has agreed not to launch Zarxio until the earlier of May 11, 2015, or the Federal Circuit’s ruling on Amgen’s request for an injunction pending an appellate decision.

Notice of First Marketing of a Biosimilar: An additional issue decided in the underlying case, also before the Federal Circuit, is whether a biosimilar applicant needs to wait until the FDA has granted marketing approval before furnishing the reference product sponsor with a BPCIA-required 180-day notice of its intent to commercially launch its product. The federal trial court answered “no” to this question and held that the notice may be given by the applicant prior to the licensure of the biosimilar product.

Conclusion

The BPCIA has opened the door for the introduction of biosimilars into the American marketplace, with interchangeable biologics certain to follow. First steps have been taken by several generics manufacturers, and product launches of these complex medicines are anticipated. Much remains to be done, however, in fine-tuning regulatory requirements and in fleshing out the statutory framework to establish a pathway for the approval and use of these necessary and high-margin products.


Alan Klein is a partner in the Philadelphia office of Duane Morris LLP and his practice focuses on products liability law and regulatory issues. Among the many products and toxic torts cases he has handled are those involving brand and generic pharmaceuticals, over-the-counter drugs, ephedra, and medical and dental devices and equipment. He can be contacted at aklein@duanemorris.com or 215.979.1150.

Disclaimer: This article is prepared and published for informational purposes only and should not be construed as legal advice. The views expressed in this article are those of the author and do not necessarily reflect the views of the author’s law firm or its individual partners.