recently undergone a bone marrow transplant. The US is fairly late to the biosimilars game. The European Medicines Agency approved its first biosimilar drug in 2006, and now there are more than 20 biosimilars available in the EU. In fact, Zarxio (as Zarzio is known in Europe) is the first biosimilar in the EU to overtake its reference product in terms of market share.
With many blockbuster biologics either soon to lose patent protection in the US or having already fallen over the patent cliff (Neupogen lost patent protection in the US in 2013), this year we’re likely to see many more applications with the FDA for biosimilar approval. What lessons can those applicants take from Zarzio’s approval process?
As it has already received marketing approval in more than 40 countries, creating a substantial amount of clinical data, Zarzio is ahead of the game in many ways.
“Zarzio is very lucky to have so much data,” says Patrice Jean, a partner at law firm Kenyon & Kenyon in New York.
“If there’s one lesson for biosimilar makers in countries that already have a lot of experimental data, it would be to get their ducks in a row and get their experimental data ready to use at the FDA so that they can get their products approved very quickly.”
However, given the complexity of biological drugs compared to small molecule pharmaceuticals, FDA approvals for biosimilars are likely to be considered on a case-by-case basis.
Courtenay Brinckerhoff, partner at law firm Foley & Lardner in Washington, DC, says that some biosimilars will be simpler than others, and that the amount of guidance biosimilar makers may take from Zarzio’s journey will depend on how much of the approval process is transparent to the public.
Te approval pathway for biosimilars will differ enormously from that of generic pharmaceuticals, which have far simpler reference products.
Under the 1984 Hatch-Waxman Act, a generic drug maker can quickly determine what patents cover the reference drug that it seeks to make, by using the FDA’s Orange Book.
However, the biologics counterpart to the Orange Book, the Purple Book, does not list patents, so it will take biosimilar applicants longer to exchange information with the biologic maker in accordance with the BPCIA, in a process that has been branded a ‘patent dance’.
Te biosimilar maker will provide the reference product maker with a confidential
notice of its intent to make a version of its biologic, then the reference product maker will provide a list of patents that it either believes will be infringed by the product, or that it would be willing to license. To date, this process has not been tested.
Biosimilar litigation has so far come in the form of declaratory judgment actions—pre- emptive suits filed by biosimilar makers at district courts that allege the originators’ patents are invalid and unenforceable. Te originators have so far not been the aggressors in court, Jean notes, as no biosimilar has yet been approved in the US.
One of these declaratory judgment actions was filed by Sandoz in 2013 against Amgen and Roche at the US District Court for the District of Massachusetts. Sandoz alleged that two patents covering rheumatoid arthritis drug Enbrel (etanercept) are invalid and unenforceable, and would not be infringed by its biosimilar. Te case was dismissed as ‘not ripe’, as Sandoz had not filed an application for the biosimilar’s approval under the BPCIA. On appeal, the US Court of Appeals for the Federal Circuit in late 2014 threw out the case, affirming the lower court’s findings. Anthony Sabatelli, a partner at law firm Dilworth IP in Connecticut, says that the appeals court failed to address the questions of whether a biosimilar developer must go through the complex patent infringement adjudication requirements of the BPCIA, or whether other litigation options are available.
Successful litigation may not be likely until the biosimilar maker has either filed its application for approval or, at least, the product is far enough down the development pipeline, he says.
Celltrion’s declaratory judgment case against Johnson & Johnson, however, may shed some light on this.
With its proposed version of Johnson & Johnson’s Remicade (infliximab), which it will market as Remsima, Celltrion may have the next biosimilar product in line. Remicade treats disorders including Crohn’s disease, rheumatoid arthritis and psoriasis. Celltrion filed its application for FDA approval of the drug last August, aſter filing for a declaratory judgment against Johnson & Johnson at the US District Court for the District of Massachusetts in March 2014. Jean says it will be interesting to watch out for the outcome of this case, as Johnson & Johnson has argued that Celltrion’s case isn’t ripe, even though it had filed an FDA application—something Sandoz had not done in the Enbrel case.
“One of Johnson & Johnson’s arguments was that the Celltrion case still isn’t ripe because there’s still no FDA approval and their approval may be years away,” she says.
SARAH BEAN /
SHUTTERSTOCK.COM
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