Biosimilar biologics: is the US being left behind?
Approval of biosimilar biologics continues to be a topic of great interest as the push for accessibility to cheaper biologic medicines continues. Globally, the clear leader in the area is the European Medicines Agency (EMA), with the US Food and Drug Administration (FDA) lagging considerably behind. To look at these contrasting situations, one may think that Europe is taking one step forward, while the US takes two steps back.
The wait for approval of a biosimilar biologic goes on in the US. Since passage of the Patient Protection and Affordable Care Act on March 23, 2010, the FDA has been in the process of implementing an abbreviated licensure pathway for biosimilars. The FDA released several draft guidance documents related to the approval pathway in February 2012.
These guidance documents dealt with (1) scientific considerations in demonstrating biosimilarity to a reference product; (2) quality considerations in demonstrating biosimilarity to a reference protein product; and (3) questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009, aka the Biosimilars Act.
The latest guidance document, entitled “Formal meetings between the FDA and biosimilar biological product sponsors or applicants,” deals with the process governing formal meetings between the FDA and biosimilar biological product sponsors. That guidance document was issued in March of this year. To date, the FDA has not approved (nor has anyone filed) a Section 351(k) biosimilar application pursuant to the Biosimilars Act.
No doubt frustrating to those who have been awaiting the approval of biosimilars in the US have been recent efforts to delay their approval. In April 2012, Abbott Laboratories filed a citizen petition with the FDA attempting to stall biosimilar approval.
Abbott requested that the FDA not even discuss with any company, much less approve, any biosimilar application or investigational new drug application that cites as its reference product any product for which approval was sought from the FDA prior to the date on which the Biosimilars Act was enacted.
The FDA has not yet substantively responded to the petition, but it has been moving forward with informal meetings. The implication is that that it has informally rejected Abbott’s petition.
Legislation
A more recent development is that many states, most notably California, have begun passing legislation trying to regulate when pharmacists can substitute a biosimilar for a prescribed biologic. The bill in California (SB-598) would authorise a pharmacist to select a biosimilar when filling a prescription order for a prescribed biological product, provided that the prescriber did not personally indicate “Do not substitute”.
The legislation would also require that the substitution of a biosimilar be communicated to the patient, and that the pharmacy notify the prescriber of the substitution or enter the substitution into a patient record within five business days of the selection. To date, the bill has not been signed by California governor Jerry Brown.
These types of state legislation are viewed differently by the Biotechnology Industry Organization (BIO) and the Generic Pharmaceutical Association (GPhA). In response to the California bill, Jim Greenwood, president and chief executive of BIO stated, “I commend California’s Assembly and Senate for overwhelmingly passing legislation that creates a pathway for the substitution of interchangeable biologic medicines.
"As the policies outlined in Senate Bill 598 align with BIO’s principles on biologic substitution, BIO supports this important legislation and encourages Governor Brown to sign the bill when it reaches his desk. BIO is pleased that the California legislature passed this legislation and continues to put patients first.”
“EFFORTS TO UNDERMINE TRUST IN THESE PRODUCTS ARE WORRISOME AND REPRESENT A DISSERVICE TO PATIENTS WHO COULD BENEFIT FROM THESE LOWER-COST TREATMENTS.”
GPhA had a directly conflicting viewpoint, arguing that the bill creates a burden on the pharmacist to substitute a biosimilar for a biologic and thus makes it more difficult or maybe less likely a pharmacist will do so. In fact, this type of legislation prompted FDA commissioner Margaret Hamburg to comment that “efforts to undermine trust in these products are worrisome and represent a disservice to patients who could benefit from these lower-cost treatments.”
As of August 2013, four states—Oregon, Utah, Virginia, and North Dakota—have passed legislation specifying requirements for biosimilars. Ten states—Arizona, Arkansas, Colorado, Delaware, Indiana, Illinois, Maryland, Mississippi, Texas, and Washington State—have introduced but not passed such biosimilar legislation. Legislation is pending in Massachusetts and Pennsylvania, while Florida is the only state to have passed a law that promotes access to biosimilars without physician notification requirements.
That said, biosimilar sponsors are definitely forging ahead with development and look to be poised to introduce the first biosimilar application in the US. According to one report, FDA “continues to meet with sponsors interested in developing biosimilar products” and as of the last week of August 2013, the agency “had received 57 meeting requests for an initial meeting to discuss biosimilar development programs for 13 different reference products and held 47 initial meetings with sponsors.”
Further evidence that it is only a matter of time came earlier this year when Amgen Inc and Hoffmann-La Roche Inc were sued by Sandoz which alleged that its generic form of arthritis drug Enbrel (etanercept) is not infringing two of Amgen’s patents, and further that a delay in the patents’ issuance renders them invalid.
The picture for biosimilars in Europe is almost completely opposite to what is happening in the US. While uptake of biosimilars into the marketplace varies across the individual countries, there are 17 approved biosimilar products on the market in Europe. These products include biosimilar epoetin alfa, interferon alfa-2a, filgrastim, somatropin, epoetin zeta, and infliximab.
On September 10, 2013, the European Commission made healthcare history with its first approval of a biosimilar monoclonal antibody, Inflectra (infliximab), which was developed by South Korea’s Celltrion and will be sold by Hospira. But even with approval in the EU, the companies do not expect to file for US approval until 2015 because they are waiting for the FDA to finalise its regulatory pathway.
What makes the approval of Inflectra so noteworthy is that monoclonal antibodies are extremely complex biologics, almost 1,000 times larger than a small molecule such as aspirin. The demonstration of biosimilarity in a complex molecule such as a monoclonal antibody, in comparison to a smaller biologic such as insulin, or even aspirin, is remarkable, at least in part because of the complex nature of their manufacture.
It is not clear what the global future will hold for biosimilars, but as it stands now, Europe continues to forge ahead with approval of increasingly complex biologics, while the US seems to be in a bit of a holding pattern as the final pieces of the regulatory puzzle for biosimilars fall into place.
Disclaimer: The views expressed herein are those of the author and should not be attributed to former, present, or future clients or any employees of Sterne, Kessler, Goldstein & Fox PLLC.
Paul Calvo is a director in the biotechnology/chemical group at Sterne, Kessler, Goldstein & Fox PLLC. He can be reached at: pcalvo@skgf.com
