The Biologics Price Competition and Innovation Act (BPCIA) deferred to the Food and Drug Administration with regard to implementing the particulars of how the biosimilar approval pathway would be implemented. The U.S. Food and Drug Administration has issued a series of draft Guidances indicating how it was considering implementing the biosimilar approval pathway contained in the Act. The Guidances were expressly “draft” in nature, and were the subject of public hearings with the Agency welcoming industry input. This input was necessary; even a cursory review of the pathway provisions of the law would strike one with the frequency with which Congress delegated to the FDA the details of setting out the requirements for biosimilar approval. This did not come as a shock, it being rational that Congress should recognize that Agency expertise was particularly important in developing standards for approving drugs as complex as biosimilars under circumstances where the “follow-on biologic” drugs were frankly not identical to the approved reference biologic product.
In April the Agency released “final” Guidances entitled:
- Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
- Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product
- Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
The FDA has released an additional, more explicit Guidance related to the requirements for establishing biosimilarity since promulgating these first three as well as a Guidance on market exclusivity. This most recent Guidance is more specific, being directed particularly to the type and amount of clinical pharmacology data the Agency will require to demonstrate biosimilarity to a reference product but is expressly “being distributed for comment purposes only” and thus how the FDA will administer the BPCIA remains a work in progress.
Provisional or not, in April the FDA approved a biosimilar version of Amgen’s Neupogen® (filgrastim) product for sale in the U.S. by Sandoz (a division of Novartis). This is the first biosimilar to be approved under the provisions of the BPCIA and will be sold under the brand name Zarxio™. The drug is a recombinantly produced version of human granulocyte colony stimulating factor (methionyl-human granulocyte colony stimulating factor or r-metHuG-CSF) and is used to stimulate neutrophil production in patients undergoing chemotherapy. Amgen has obtained FDA approval for Neupogen® for treating the following five conditions:
- Cancer patients receiving myelosuppressive chemotherapy;
- Cancer patients with acute myeloid leukemia receiving induction or consolidation chemotherapy;
- Cancer patients undergoing bone marrow transplantation;
- Patients undergoing autologous peripheral blood progenitor cell collection and therapy; and
- Patients with severe chronic neutropenia.
Sandoz provided the FDA with a wide variety of evidence of biosimilarity since it filed its application under Section 351(k) of the Public Health Service Act last July; this evidence included “structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data” and, importantly, an absence of immunogenicity in human subjects, together demonstrating the biosimilarity of Sandoz product Neupogen® according to the FiercePharma website. In particular, Sandoz performed a head-to-head comparison between its biosimilar drug and Neupogen® showing a level of biosimilarity sufficient for the FDA to approve Zarxio™ for all of Amgen’s approved indications.
Approval of Zarxio™ is significant because, as the first biosimilar approved, it will be a bellwether for how well the FDA has implemented the BPCIA and performed in its role in protecting public health. The complexity of both biologic drugs themselves (which typically comprise thousands of atoms; the chemical formula of filgrastim for example is C845H1343N223O243S9) and the methods by which they are made (typically using recombinant cells expressing genetically engineered genes transferred from one organism (here, human) to another such as bacteria) provide much greater challenges for the agency in performing its review of safety, potency and efficacy. While the EMEA in Europe has successfully approved biosimilar drugs for a decade, in the U.S. doubts are likely to remain until experience (both the agency’s and the public’s) has shown them to be unfounded.
One thing the FDA did not do was approve Zarxio™ as an interchangeable product, because inter alia the agency has not yet developed standards for making this determination. In addition to the absence of “no clinically meaningful differences” required to be shown between the branded (or reference product sponsor’s) product and the biosimilar drug for approval as a biosimilar, to be interchangeable there must be no differences in outcomes when a patient is switched to an interchangeable biosimilar drug product than occur when the innovator’s product is administered. Interchangeability when achieved will have the advantage that switching to the interchangeable version will not require physician approval and will be eligible for at least a one-year exclusivity period for the successful interchangeable biosimilar applicant.
This is but the first of many biosimilar approvals waiting FDA action; these include applications by Apotex for its version of Neupogen® (which was accepted by the FDA last month and is sold in Europe under the name Grastofil) as well as a biosimilar version of Amgen’s Neulasta® (a PEGylated version of the molecule). Pundits and politicians have pontificated about the benefits to be had by adopting a biosimilar approval pathway in the U.S., and those predictions have begun the process of being tested with approval of Zarxio™.
About Kevin Noonan
Kevin Noonan is a Partner at McDonnell Boehnen Hulbert & Berghoff LLP and represents biotechnology and pharmaceutical companies, from startups to Fortune 100 companies, on a myriad of issues, as well as several universities in both patenting and licensing to outside investors. He has filed amicus briefs to district courts, the Federal Circuit and the Supreme Court involving patent issues relevant to biotechnology. Kevin is a founding author of the Patent Docs weblog where he writes frequently, and was recently named Chicago’s Biotechnology “Lawyer of the Year” by Best Lawyers in America 2013 and 2014. In 2010, Kevin was interviewed on 60 Minutes about gene patenting.