FDA Seeks to Dispense With Switching Studies for Interchangeable Biosimilars

The FDA recently took another step toward levelling the playing field between biosimilars and interchangeable biosimilars when it proposed doing away with switching studies for interchangeable products. While the draft guidance may receive some resistance, ultimately it should help provide clarity that all biosimilars are similar in their safety and efficacy, bringing these agents onto the U.S. market faster and prompting more competition among the agents, industry experts maintain.

As part of the Affordable Care Act (ACA), the Biologics Price Competition and Innovation Act of 2009 (BPCIA) amended the Public Health Service (PHS) Act and established section 351(k), which outlines the requirements for a proposed biosimilar product and a proposed interchangeable biosimilar product. Physicians must specifically prescribe biosimilars without interchangeable status, but when a biosimilar is approved as interchangeable, that drug may be substituted at the site of care or dispensing for its reference product by a dispensing pharmacist or practitioner without the involvement of the prescribing physician.

Among the conditions needed for interchangeability are that not only is the drug biosimilar to its reference drug but also that the agent “can be expected to produce the same clinical result as the reference product in any given patient” and that “for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

To satisfy that last requirement, the FDA’s initial interchangeability guidance — published on May 19, 2019, almost 10 years after the ACA’s enactment on March 23, 2010 — explained that applications for interchangeability “generally will include data from a switching study or studies in one or more appropriate conditions of use.” The guidance, titled “Considerations in Demonstrating Interchangeability With a Reference Product,” offered considerations for such studies’ design, including endpoints and analysis.

While the FDA approved the first biosimilar, Sandoz’s Zarxio (filgrastim-sndz), on March 6, 2015, it wasn’t until July 28, 2021, that it granted interchangeability to a biosimilar, Semglee (insulin glargine-yfgn), which at the time was a product from Viatris Inc. and Biocon Ltd. subsidiary Biocon Biologics Ltd.

As of early July, the FDA has approved 57 biosimilars, 15 of them with interchangeable status.

Based on the agency’s experience with these agents, on June 20 the FDA published the draft guidance “Considerations in Demonstrating Interchangeability With a Reference Product: Update.” Since the 2019 guidance, it said, “experience has shown that for the products approved as biosimilars to date, the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product. Accordingly, FDA’s scientific approach to when a switching study or studies may be needed to support a demonstration of interchangeability has evolved.”

The agency has gained experience in analyzing the “potential analytical differences” between proposed biosimilars and their reference drugs and how those impact clinical performance, it said. The guidance also notes that “currently available analytical technologies can structurally characterize highly purified therapeutic proteins and model in vivo functional effects with a high degree of specificity and sensitivity using in vitro biological and biochemical assays.”

Because of this, the FDA said, companies applying for the interchangeable designation may offer an assessment of why the comparative analytical and clinical data support the switching standard in the BPCIA. They also should include in their applications any other relevant information as far as safety and efficacy in switching between the reference drug and the biosimilar.

Companies that have a pending biosimilar application may submit an amendment to their Biologics License Application and request that the product be reviewed as a proposed interchangeable biosimilar.

The FDA clarified that the guidance was not meant as a standalone document; rather, when the recommendations are finalized, the agency will revise the interchangeability guidance, including replacing certain sections of it.

A notice on the guidance was published in the Federal Register on June 21 (89 Fed. Reg. 52060). Its comment period ends Aug. 20.

The FDA noted that of the 13 interchangeable biosimilars that it had approved at the time of the recent draft guidance, nine did not include data from a switching study.

“The recommendations in today’s draft guidance, when finalized, will provide clarity and transparency about the FDA’s thinking and align the review and approval process with existing and emerging science,” said Sarah Yim, M.D., director of the Office of Therapeutic Biologics and Biosimilars. “We have gained valuable experience reviewing both biosimilar and interchangeable biosimilar medications over the last 10 years. Both biosimilars and interchangeable biosimilars meet the same high standard of biosimilarity for FDA approval and both are as safe and effective as the reference product.”

Other Attempts Have Tried to Minimize Distinction

The move is the latest one to minimize the difference between biosimilars and interchangeable biosimilars.

In a final rule released in April, CMS said it would allow Medicare Part D sponsors to substitute any biosimilar for its reference drug following a 30-day notice. Previously, only interchangeable biosimilars could be substituted.

In March, HHS’s and the FDA’s fiscal year 2025 budgets proposed eliminating the distinction between the approvals for biosimilars and interchangeable biosimilars. Both called for amending section 351 of the PHS Act “to no longer include a separate statutory standard for a determination of interchangeability and to deem all approved biosimilars to be interchangeable with their respective reference products.”

In September, the FDA proposed including interchangeability information in the Purple Book Database of Licensed Biological Products — known simply as the Purple Book — only and not on a drug’s label, as well having the same biosimilarity statement for both biosimilars and interchangeable biosimilars on their labels.

Prior to that, in July 2023, Sen. Mike Lee (R-Utah) reintroduced the Biosimilar Red Tape Elimination Act (S. 2305). The legislation seeks to “deem biosimilars as interchangeable with their branded equivalent upon their approval by the FDA.”

The FDA also has granted the interchangeable designation to significantly more biosimilars this year alone. In 2021, one agent secured the designation, and then 2022 and 2023 each saw three biosimilars granted the designation. But in 2024, 12 biosimilars already have been approved, and eight agents have gained interchangeability, most recently Samsung Bioepis Co., Ltd. and Sandoz’s Pyzchiva (ustekinumab-ttwe), approved June 28 with a provisional determination for interchangeability due to “an unexpired period of exclusivity for the first interchangeable biosimilar biological products.”

And at the state level, four states so far — Arkansas, California, Kentucky and Louisiana — have passed legislation allowing health plans to substitute biosimilars similarly to interchangeable biosimilars and generics.

The FDA’s two-tiered biosimilar system also is at odds with that of the EU, whose European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) clarified in September 2022 that all biosimilars approved in the EU are interchangeable.

Guidance Could Speed Products to Market

If the draft guidance is finalized and biosimilar manufacturers do not need to conduct switching studies for interchangeability, this “should streamline the path for interchangeable biosimilar approval and potentially reduce development costs for the manufacturer. This could allow the biosimilars to come to market more quickly,” says Renee Rayburg, R.Ph., vice president of clinical strategy at Pharmaceutical Strategies Group (PSG), an EPIC company.

In addition to the cost savings, “biosimilar manufacturers may benefit from less access challenges, particularly if states align with the FDA guidance and permit pharmacist substitution of all biosimilars versus only those with interchangeability designation,” asserts Amy Martin, Pharm.D., vice president of the access experience team at Precision AQ.

She points out that uptake of pharmacy benefit biosimilars without interchangeable status has been a challenge due to state substitution laws. But if the proposed guidance is finalized, that may in turn result in changes to those laws. In that situation, where all biosimilars may be substituted, “reference product manufacturers will need to communicate strong value messages, [offer] competitive pricing [and] have consistent utilization performance and a clear differentiation from the biosimilars in order to compete.”

The guidance may be a downside for some companies, says Rayburg, because having interchangeable status “allows for differentiation among competitive products, which in some cases could have allowed for a competitive edge” for some biosimilar manufacturers. “That would no longer be the case with the proposed changes.”

Rayburg says that some manufacturers of reference drugs have used biosimilars’ “lack of interchangeability in their messaging as a reason to not prefer or consider certain biosimilars. This change will eliminate product differentiation, force manufacturers to compete on price alone and contribute to mainstreaming biosimilars more quickly.”

Pharmacists, Rayburg points out, will have an easier time dispensing biosimilars, including switching patients from a reference product.

All 50 states, as well as Washington, D.C. and Puerto Rico, have enacted laws around interchangeable biosimilar substitution, with policies such as informing patients and physicians when a biosimilar is substituted without a prescription for that product.

If the proposed guidance is finalized, those laws would need updated, and Martin says that she “anticipate[s] some delay with individual states updating pharmacist substitution laws.” Pharmacist notifications of other stakeholders “introduce[es] an extra step in the dispensing process and an increase in operational costs. Timely changes to state laws to permit substitution of all biosimilars can help ease access challenges faced by biosimilar manufacturers.”

Some concerns around the updated guidance may come from providers who are not as comfortable prescribing biosimilars as they are reference drugs, especially when switching patients from a reference drug to a biosimilar, states Rayburg.

But most health care professionals should still have confidence in biosimilars’ safety and efficacy if the guidance is finalized, she tells AIS Health, a division of MMIT. “Early on, the interchangeable designation did lead to some confusion and an inaccurate perception that interchangeable biosimilars are safer and more effective than those biosimilars without this designation. However, with more data from switching studies demonstrating safety and efficacy and an increase in prescribing and utilization of biosimilars, this misunderstanding has diminished. There are at least 31 studies that have shown there are no major concerns when patients have switched to biosimilars.”

Indeed, many of the oncology and supportive care biosimilars — none of which have interchangeability save for Sandoz’s Wyost (denosumab-bbdz), which was just approved in March — have managed to secure significant market share, according to Samsung Bioepis’ Biosimilar Market Report for second-quarter 2024.

“I don’t believe the FDA evolving their thinking on biosimilars undermines confidence in safety or efficacy,” agrees Martin. “Not requiring switch studies moves the U.S. closer to how the European Medicines Agency views biosimilars. In doing so, the FDA acknowledges the interchangeability designation does not indicate a higher level of biosimilarity, safety or efficacy.”

Ultimately, she says, “Making biosimilars more widely available is a generally accepted ideology. While we can anticipate feedback and questions during the comment period, I don’t expect a widescale, direct pushback to the FDA guidance.”