Amgen’s Neupogen, the first biosimilar for which has been given the FDA’s blessing. @Bayne Stanley/Alamy

Sandoz’s biosimilar drug is about to become the first drug approved under the FDA’s biosimilar pathway. On January 7, the US Food and Drug Administration’s (FDA’s) oncologic drugs advisory committee voted unanimously to recommend approval of Basel-based Sandoz’s granulocyte colony stimulating factor filgrastim, a biosimilar of Thousand Oaks, California–based Amgen’s $1.2-billion seller Neupogen. Six years after Sandoz’s biosimilar filgrastim was approved in Europe, with 7.5 million patient-exposure days to support approval, it would seem a reasonable bet that the drug, whose proposed brand name is Zarxio, will get a green light on March 8, as Nature Biotechnology goes to press.

If so, it would mark a very long-awaited victory for biosimilars developers. The FDA’s biosimilar pathway was created in 2012 under the Biologics Price Competition and Innovation Act (BPCIA) after years of wrangling with originator firms. Zarxio’s launch would be symbolic of FDA’s broader blessing—at least in principle—for a whole new generation of cost-effective products. Zarxio, if approved to treat chemotherapy-induced neutropenia and related conditions, could save $5.7 billion in drug costs over the next decade, estimates US pharmacy benefit manager Express Scripts. No wonder New York–based Pfizer on February 5 deepened its commitment to biosimilars (and other hard-to-make generics) by a $17-billion bid for Lake Forest, Illinois–based Hospira, which is involved with two of the four known biosimilar submissions to FDA.

But if approval appears likely for Zarxio, several other barriers to commercial success remain (Nat. Biotechnol. 31, 264, 2013). Indeed, given the already relatively onerous nature of the US biosimilar pathway—known as 351(k)—“if this product doesn’t successfully launch, the biosimilar pathway is killed,” according to one Washington, DC–based expert who wants to remain anonymous.

What can go wrong? If Amgen gets its way, the courts could block, or at least delay, Sandoz (a division of Novartis) from launching. Amgen has thrown various accusations at the Swiss firm, ranging from not following the BPCIA rules over sharing information about its submission, to outright patent infringement.

Litigation aside, there remain unanswered questions around the product’s generic name and its label, just weeks away from the March 8 PDUFA (Prescription Drug User Fee Act) date. It’s unclear whether Zarxio will enjoy the same international nonproprietary (INN) name as the originator drug. FDA has yet to issue its promised guidance on biosimilar naming and faces strong pressure from innovator companies to mandate distinct INNs for each biosimilar product, purportedly to facilitate adverse event tracking. But ODAC member James Liebmann declared that the group had reviewed the drug as “filgrastim,” and that calling it anything else would be misleading. Sandoz agrees, pointing to the many US-marketed biologics that currently share an INN without any safety or traceability issues. “We’re sticking to our position that a brand name is the most useful” and that creating a new naming system is completely unwarranted, says a Sandoz spokesman.

FDA is unlikely to insist upon a completely different INN for Zarxio, but could suggest a hyphenated name, speculates Ronny Gal, a senior analyst at Sanford C. Bernstein in New York. A prefix wouldn’t be a disaster—Petah Tikva, Israel–based Teva’s long-acting Granix (filgrastim), approved as a novel biologic and launched in late 2013 as TBO-filgrastim, has about 15% market share by volume. But it would put another brake on the likely uphill battle convincing clinicians that the drug is clinically the same as Neupogen. It could also create headaches for pharmacy IT systems, including, for example, on alphabetical medication lists where the product would not appear with other filgrastims.

Sandoz doesn’t yet know how similar Zarxio’s label will be to the originator drug’s either. Biosimilar firms can apply for their products to be labeled ‘interchangeable’ with the originator drug—a designation that ostensibly supports automatic substitution by pharmacists, though several states have passed laws banning such action anyway (Nat. Biotechnol. 31, 269–270, 2013). For now, on FDA’s advice, Sandoz hasn’t applied for interchangeability; filgrastim is mainly a hospital-administered drug, anyway. But FDA may do so in future. “The standard for that [interchangeability] will include several years of real world use of the biosimilar, at least for the first ones,” opines Michael McCaughan, co-founder at Washington, DC–based information services firm Prevision Policy. But whether Zarxio is in the meantime labeled “noninterchangeable,” playing into the hands of those seeking to block widespread biosimilar uptake, remains to be seen. “Drugs aren’t normally labeled for what they’re not,” says Gillian Woollett, senior vice president FDA Regulatory Strategy and Policy at Avalere Health in Washington, DC. But there’s little that’s normal or straightforward so far about the road to biosimilar approval in the US.

The fact that an advisory panel was called at all is the first clear sign that this class of products won’t sail onto the market without very close scrutiny; small-molecule generic drugs aren’t typically subject to advisory committees. But as FDA’s Center for Drug Evaluation & Research director Janet Woodcock noted in opening remarks during the agency’s advisory committee meeting on Zarxio biosimilars represent “a different kind of development program” from what the agency has seen before. The unanimous vote in favor of Zarxio’s approval across all five of Neupogen’s licensed indications belies a detailed discussion within the  committee  as  to  whether  the  product could be deemed “biosimilar”—that is to say, with “no clinically meaningful differences… in terms of safety, purity and potency,” according to the agency’s definition.  The vote has been presented as a slam dunk, but there was much discussion leading up to it.

That’s not surprising, though. FDA advisory panels comprise mostly clinicians, accustomed to assessing clinical trials for safety and effec-tiveness, not to scrutinizing reams of analytical data and chemistry manufacturing and controls issues to determine biosimilarity. “A cognitive change has to occur within the agency, the pharmaceutical industry, and in the minds of clinicians and patients,” notes Leah Christl, FDA’s associate director for therapeutic biologics. Indeed, FDA officials were “highly supportive” of Novartis and its application, writes Prevision Policy co-founder Ramsey Baghdadi in a January 7 research note, and “steered the committee away from letting minor concerns turn into major hurdles.”

Still, warns Sanford C. Bernstein’s Ronny Gal, if advisory committees become a regular feature of biosimilar reviews, “their composition will have to change to include more protein scientists and animal pharmacologists. If they continue to focus on phase 3 data, it will be tougher for biosimilars to go through.”

Sandoz isn’t hanging around for the uncertainties to be resolved. Launching this first biosimilar will require the same kind of marketing and educational support as a branded drug, at least for now. Zarzio, as the drug is called in Europe, benefited from such preparedness and is now the region’s leading daily filgrastim, with 30% volume market share. Sandoz believes the US system will eventually adopt products that can save costs. Indeed, FDA’s Woodcock’s remarks at the committee included likening the potential impact of biosimilars on the healthcare system to that of small-molecule generics. Zarxio’s approval won’t open the floodgates to US biosimilars. The next in line for approval is an infliximab biosimilar made by Incheon, Korea–based Celltrion, with Hospira as the exclusive commercialization partner. It is a copy of Johnson & Johnson’s rheumatoid arthritis drug Remicade and is a far more complex molecule than filgrastim. Also, it lacks the extensive usage data that Sandoz was able to show for Zarxio, which is believed to have reassured the panel, regardless of the strength of the analytical data. Celltrion and Hospira have been selling biosimilar infliximab (as Remsima and Inflectra) in Europe only since September 2013, and only in some Central and Eastern European markets.

Infliximab’s review will test how far FDA is prepared to go in allowing extrapolation between indications. Remicade is indicated for eight very different  diseases,  including  rheumatoid  arthritis,  Crohn’s  disease and ulcerative colitis. In Europe, the biosimilar was approved for these indications, based on clinical trial data from only two. That might be tougher to achieve in the US, where the drug will face a biosimilar-naive Arthritis Advisory Committee. Toronto-based Apotex and Ahmedabad, India–based Intas Biopharmaceuticals with a biosimilar of Amgen’s Neulasta (pegfilgrastim) and Hospira with a biosimilar of Amgen’s Epogen (epoetin alfa) are the two other known applicants.

Amgen, facing biosimilar assaults on several of its products, announced its own biosimilar development pipeline. Even without that, though, the company will likely use bundling and rebates to leverage its portfolio and market position and defend against any single biosimilar competitor. “It will take time for the first biosimilar to gain share. If Zarxio gets to 30% in three years, it would be a good result,” says Gal.

Melanie Senior London