Legislation & Regulation

Wait Time for Biosimilar Regs Drags On

It seems like Godot may arrive sooner. Seven years after the biosimilar law was enacted, stakeholders are losing patience with the FDA.

Richard Mark Kirkner

Last year, when the FDA approved filgrastim-sndz (Zarxio) as a biosimilar to filgrastim (Neupogen), a biologic that stimulates the production of white blood cells, many in the biopharma industry thought maybe, just maybe, that the regulatory spigot was finally opening for biosimilars.

A drop does not a flow make. Since then the agency has not approved a single biosimilar, not a one, although in fairness an FDA panel did recommended approval of a biosimilar form of infliximab (Remicade) in February.

The FDA’s foot-dragging on drafting regulations on biosimilars, as spelled out in the Biologics Price Competition and Innovation Act (BPCIA) of 2009, has frustrated and confounded not only the biopharma industry, but also the public, health plans, and pharmacy benefit managers because potential lower-cost competitors to expensive biological agents are stalled in the regulatory pipeline. Key senators are in that mix, too. Last year a Senate committee grilled Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, on why, six years on, the agency hasn’t been able to come up with the regulations for biosimilars.

Similar, not identical

In the market, the biologics are supposed to serve the same function as generics for small-molecule medications: Drive down prices by creating an unbranded alternative. But whereas the active agent in generics are identical to the patented agent, biosimilars are, well, similar, as Kay Holcombe, senior vice president for science policy at the Biotechnology Innovation Organization (BIO), explains it. “Biosimilars are not worse than their reference product, they are not better than their reference product, but they are not identical either; they are similar,” she says. Hence the BPCIA set up a regulatory pathway separate from that for small molecule drugs.

Katie Holcomb

Savings for biosimilars are “difficult to project given the many uncertainties that still exist regarding market penetration and price,” contends Katie Holcomb of Milliman.

Biosimilars are in the limelight because expensive biological agents have put such a strain on the health care system. A 2014 Rand Corp. report predicted that biosimilars could reduce U.S. spending on biologics by $44.2 billion over the next eight years—about 4% of total spending on biologic therapies. A Milliman white paper detailed the potential savings of biosimilars. “Savings are difficult to project given the many uncertainties that still exist regarding market penetration and price; however, we project savings of 0.3% to 0.8% of total health care expenditures by 2019 for a typical commercial employer,” says Milliman actuary Katie Holcomb. (Speaking of similarity, it’s just a coincidence that we ended up talking with two people with similar names for this column.)

But savings will only happen if the FDA gets its regulatory act together.

What’s in a name?

The naming of biosimilar agents has kicked up plenty of controversy. The core question is whether they should have the same molecule name as the branded reference product.

The FDA actually did make some headway on naming last year when it issued draft guidance. According to the guidance, a biosimilar should have a distinguishable name that includes the same active drug name as the reference biologic but would have a suffix that would allow doctors, pharmacists, and patients to know what variation of the biologic agent they’re getting. The rationale is that this would allow the FDA to trace adverse events after the product gets approved.

That’s the position the likes of BIO and the Pharmaceutical Research and Manufacturers of America have staked out and prefer. “We believe that all biological products should have distinguishable names, so that the provider in particular, as well as the dispenser of the product, will understand clearly what’s being provided to the patient,” says BIO’s Holcombe.

Unnecessary confusion

“Each side is looking to protect its own interest,” counters Jeffrey Casberg, a registered pharmacist and director of clinical pharmacy for IPD Analytics, a research firm in suburban Miami. A naming convention that does not align with the original chemical name or adds a prefix or suffix that has no meaning would create unnecessary confusion, he says.

Casberg and others favor following the World Health Organization’s International Non­proprietary Name (INN) convention for naming medications with no FDA-designated suffix. The biosimilar and the branded product’s generic name would be the same. So, for example, it would be filgrastim and filgrastim, not filgrastim and filgrastim-sndz.

That position—an INN name with no “FDA-designated suffix”—is the one backed by AHIP and, no surprise, the Generic Pharmaceutical Association’s (GPhA) Biosimilars Council. The FDA draft guidance, however, makes no mention of the INN. In the United States, another group, the United States Adopted Names Council, acts as a naming gatekeeper, although it works closely with the WHO program.

Biosimilar companies and others say the FDA doesn’t need a name difference to keep track of biosimilars and any untoward effects that they might have. When the FDA unveiled its naming guidance last year, Bertrand Liang, chair of GPhA’s Biosimilars Council and CEO of Pfenex Inc., a biosimilar development company in San Diego, countered that the agency can monitor postmarket adverse events using the national drug code, lot number, and company name. He also noted other countries are already allowing biosimilars and their reference products to share an INN name without any patient safety issues.

“Adding a random collection of letters to the product’s nonproprietary name confers no additional safety benefit, and in fact would require the health care professional to be armed at all times with a code-breaking reference,” Liang argues.

What does “interchangeability” mean?

Most people consider interchangeability akin to substitution. In many states, for example, the pharmacist can switch a prescription from a brand-name drug to a generic medication as long as the prescriber leaves the “no substitution” box on the prescription unchecked. With biosimilars, it’s not that straightforward—again, because of their similarity versus being deemed identical. FDA guidance on interchangeability is a big missing piece of the regulatory puzzle. The biopharma industry is expecting it to be filled this year.

The BPCIA created two biosimilar pathways: 351(k)(2)(A) for non-interchangeable biologics, the provision under which Zarxio got approval; and 351(k)(2)(B) for interchangeable ones. But for interchangeability, it’s really a two-step process, as BIO’s Holcombe explains: “So the FDA makes one decision—yes, the product is biosimilar to the reference drug; and then a separate decision—yes, the product is interchangeable,” she says.

Interchangeability is tricky business. For one thing, a drug might be deemed a biosimilar but interchangeable for only one of the indications of the reference biologic.

Jeffrey Casberg

What additional studies will the FDA require to prove interchangeability? That’s just one of the questions that raises the stakes for companies that want to make biosimilars, says Jeffrey Casberg of IPD Analytics.

FDA regulatory guidance might help clear up some of the knotty issues involved in interchangeability. “When you have two products that are similar but not identical, the question is, what are the key things the FDA is going to look at to make that second decision” about interchangeability? says Holcombe.

For companies that make biosimilars, the stakes are high. If a product has been on the market, Casberg asks, will the company hesitate to apply for interchangeability for fear of public fallout if the application gets turned down? What additional studies will the FDA require to prove interchangeability?

States decide substitution rules

While the FDA designates whether a biosimilar is interchangeable with its reference agent, it’s up to states to regulate whether a pharmacist can substitute an interchangeable biosimilar for a reference biologic agent.

Eighteen states have such laws and 11 more are pending. The state laws vary, but many include provisions that would give the prescriber the power to prevent substitution by stating “dispense as written” or “brand medically necessary” and that the prescriber must be notified of any allowable substitution made at a pharmacy.

But until the FDA provides a policy and a biosimilar receives an interchangeability rating, those laws could be collecting a lot of dust.

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Legislation and regulation
By Richard Mark Kirkner
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