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Amgen Executive Weighs the Challenges for Interchangeable Biosimilars


A turning point for interchangeable biosimilars has arrived, as the first may be approved this year, but many questions about these agents have yet to be answered, according to Laura Sim, senior counsel for Amgen.

It’s very likely that 2021 will be the year of the first interchangeable biosimilar, which pharmacists could substitute for an originator brand without asking the prescribing physician for approval. Expectations are that the FDA will approve at least 1 this year.

As of April 2021, all US states had passed laws for how and when these can be used, according to Laura Sim, senior counsel for Development, Regulatory, Operations, and Contracting Law at Amgen.

All of these will allow pharmacists to dispense interchangeable biosimilars, provided the physicians have not stated that originator brands should be used, and some record of the interchangeable being prescribed must be made available to physicians.

“A lot of the state laws also require that the patient be notified before the substitution takes place,” she said.

In some instances, these laws contain “sunset,” or automatic termination, clauses, which expire if they aren't reauthorized, which enables public officials to reconsider them, Sim said in a presentation at the American Cancer Institute’s 12th Annual Summit on Biosimilars and Innovator Biologics, held June 22-23, 2021. This is a sign of the great uncertainty that still surrounds interchangeable biosimilars and their pending debut, she noted.

“This area is still clearly developing on the regulatory side, and there are unknowns on the commercial implications of interchangeability; the next 3 to 5 years are going to be a critical, pivotal time for starting to really gauge how interchangeability will play out and the value it will have,” she said.

An FDA biosimilar approval is a declaration that the biosimilar is as safe and efficacious as the originator biologic it references, with no clinically meaningful differences, but to qualify as interchangeable biosimilars must go through additional regulatory hoops, such as switching studies to demonstrate that patients will have the same clinical outcomes whether they start on the reference drug and switch to the biosimilar or switch back to the reference drug after using the biosimilar.

An area that's pretty important that we haven't had definitive input yet from the FDA is what will be the durability of an interchangeability designation? Are there circumstances that could cause FDA to revisit whether an interchangeability designation should stand?

“It’s important to note that interchangeability does not confer any sort of clinical superiority. It does not mean any sort of higher quality vs biosimilars that have not received an interchangeability designation,” Sim said.

The FDA has indicated in recent guidance that a switching study generally will be expected to support an interchangeability designation and a sponsor should provide scientific justification for use of that product in a non–FDA-approved indication.

Product Advances

Having even that information won't erase the question marks hovering over the interchangeable designation, Sim said. What happens if an application device for a biosimilar is different from the type used for the originator? And what happens as different formulations of the biosimilar or originator are developed after an interchangeable designation has been assigned?

“What evidence is the FDA going to ask for to support those differences?” Sim asked. “Another area that’s pretty important that we haven’t had definitive input yet from the FDA is what will be the durability of an interchangeability designation? Are there circumstances that could cause the FDA to revisit whether an interchangeability designation should stand? For example, if the reference product and the interchangeable product drift apart over time, [biologics differ minutely batch to batch].”

“We also don't know if companies will be allowed to include in their label any data that they generated to support the interchangeability designation,” Sim said.

What remains to be seen is what are going to be the payer reimbursement inputs? Are payers going to look at interchangeability as a differentiator? How much weight is it going to hold in their deliberations?

Another question is how payers will react to the interchangeability designation. Will they give it more weight when they consider a drug for formulary placement? “I think we’re going to start to get some answers to these questions, or some early indications of how payers are thinking, in the next few years,” She said. 

Interchangeable Insulins

On March 23, 2020, insulins and growth hormones began to be regulated under the Biologics Price Competition and Innovation Act, and this means that they, too, could be approved as biosimilars and interchangeables. But for insulins, the requirements for an interchangeable designation are far less stringent.

These agents are less complex than the typical monoclonal antibody biosimilar, and more is known about them via historical usage and development, so the FDA has indicated in guidance that it is comfortable not requiring clinical immunogenicity studies or switching studies to support interchangeable designations for these products, Sim noted.

“This is really a pretty big deviation from how the FDA has traditionally approached biosimilars and how they’ve approached other product areas,” she said. “It really pares back the expectations for clinical testing, but it’s in this narrow class of insulins, which is a fairly unique product class in a number of ways. And I do think it raises the question, at least, whether this may be a sign of some things to come potentially for other small, well-characterized [small molecule] biologics.”

Ultimately, the debate over the interchangeability designation will play out in the public forum, she said. “I think it’s fair to expect that we’ll have some litigation and some citizen petitions and the like over interchangeability designations. If we look at the generic space, a lot of these issues can be very contentious.”

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