When US regulators approved a new drug called Zarxio in March, it became the first FDA-approved biosimilar: a “copy” of a medication made from living things.
Drugs derived from biological substances like immune cells are major money-makers for pharmaceutical companies, representing most of the top ten best-selling pharmaceuticals. Unlike simple chemical formulations like Advil, these complex biologics cannot be turned into generic drugs even when their patents expire.
By definition, biosimilars mimic the activity and safety of the original biologics they are based on, but the original and the “copy” are not chemically identical. They are not necessarily produced in the same way, often representing a different means to a similar end.
That makes them much trickier and more costly to develop than traditional generics, but they are seen as a huge opportunity both for the companies pursuing them and potentially for the healthcare system, which could save billions when cheaper options of some of the most expensive drugs on the market become available.
It’s because of all that complexity that biosimilars’ game-changing potential could trip over some still-significant challenges.
The “similar” in biosimilar
Ultimately, drugmakers want to go further than “biosimilar;” they want to achieve “interchangeability.”
When the Affordable Care Act opened up a pathway for the FDA to approve drugs that mimic off-patent biologics, it created two tiers: products that are biosimilar — “highly similar [to the original product… [with] no clinically meaningful differences” — and those that are interchangeable, which would be held to even higher standards.
To be considered “interchangeable,” biosimilars must (along with some other requirements) “be expected to produce the same clinical result as the reference product in any given patient,” according to the Biologics Price Competition and Innovation Act of 2009. Drugs designated as “interchangeable” also must show that a patient could switch back and forth between the original product and the biosimilar without any increased risk.
While biosimilars are expected to shake up the market, interchangeables would have the potential to be even more transformative by precipitating a much steeper drop in costs, according to a Health Affairs analysis.
How? Hypothetically, biosimilars designated as “interchangeable” could be swapped out at the level of the pharmacy, without any required input from a doctor. That means Medicare or insurance companies could make an interchangeable biosimilar the only covered option when one is available, leading to potentially significant cost savings for the health system as a whole. (While biologics are usually administered under a doctor’s close supervision, this pharmacy-level substitution is already what happens with traditional generics, which can be swapped in unless a doctor checks the “do not substitute” box on a prescription.)
So far — while industry groups say companies will push for an “interchangeable” designation on a case-by-case basis — no drug has met the standards for interchangeability.
Why interchangeable might be impossible
In a 2014 paper, Hans Ebbers, a researcher at Utrecht University in the Netherlands and an expert on biosimilars, asked whether the challenge of achieving interchangeability was an “insurmountable” hurdle.
It’s a question worth asking, even though the answer is complex.
The idea that an interchangeable biosimilar must perform the same in “any given patient” is part of what makes achieving interchangeability so tricky, because that’s not exactly how studies on new biotech drugs work, Ebbers explains in the paper. “Such studies will only be able to address comparability on an aggregated (population) level,” he writes — not in every individual patient.
In the meantime, rules against swapping in a biosimilar for the original product it’s based on “could be misinterpreted by prescribers to indicate that switching to a biosimilar might lead to unsafe situations,” Ebbers and colleagues wrote in a Nature Biotechnology commentary. That’s true even though according to the FDA’s rules, both biosimilars and interchangeables should “have no clinically meaningful differences in terms of safety” when compared to the original drug.
Still, some safety issues only surface after a drug is widely prescribed. As more biosimilars approved in the US, they will be “watched very closely” for any adverse events, Jerold Martin of Pall Life Sciences noted recently at a session on biosimilars at
INTERPHEX, an industry conference. Until biosimilars are considered as interchangeable as ibuprofen and Advil, there could be some major issues with widespread adoption.
Manufacturers, however, are intent on achieving that very scenario.
“Interchangeability is the holy grail for the biosimilar market,” said Parrish Galliher of GE Healthcare recently, at INTERPHEX. It’s what will free biosimilar manufacturers from “any objections from pharmacists and physicians.” Without that, he explained, “they will need a stronger marketing team.”
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