Biosimilar Interchangeability: NOR-SWITCH-Type Study Not Enough For US FDA

Norwegian single-transition study would not satisfy agency's requirements for demonstrating interchangeability but could boost patient confidence in general concept of switching between reference product and biosimilar.

The landmark NOR-SWITCH study may help bolster public confidence in biosimilars even though this type of study would not be enough to secure an interchangeability designation from the US FDA, experts said at a DIA biosimilars conference.

FDA does not consider a study akin to NOR-SWITCH, which involved a single transition from a reference product to a biosimilar, adequate to support an interchangeability determination, according to Leah Christl, associate director for therapeutic biologics in FDA's Center for Drug Evaluation and Research.

Rather, the agency is already requesting this type of single-transition data for applications seeking biosimilar approval, not interchangeability determinations, she said Oct. 28.

NOR-SWITCH "would not be an adequate study design" to support interchangeability "in and of itself." – FDA's Christl

"The evaluation of a single transition is not something that would support interchangeability in and of itself," Christl said. "That would not be an adequate study design."

However, the value of the Norwegian study involving Celltrion Inc.'s Remsima and Janssen Biotech Inc.'s Remicade (infliximab) may lie in the reassurance it provides patients who are concerned about the idea of switching between a reference product and a biosimilar in general, said Hillel Cohen, executive director for scientific affairs at Sandoz Inc.

NOR-SWITCH shows that patients "shouldn't be afraid of the act of switching by itself," Cohen said. "I think the value is more how the public perception may begin to switch – pun intended."

A Positive Study …

FDA has yet to publicly lay out its data expectations for interchangeability determinations. Under the Biosimilar User Fee Act reauthorization agreement negotiated with industry, the agency has committed to issue a draft guidance on interchangeability by the end of 2017, although agency officials said they continue to hope that such a document is released in 2016. (Also see "Biosimilar Guidance Development Timelines Criticized By Docs And Patients" - Pink Sheet, 20 Oct, 2016.)

In the absence of formal guidance, the agency has talked to biosimilar sponsors about the evidence needed for interchangeability in the context of individual development programs. However, such discussions have occurred in private, thereby creating a transparency gap into the agency's thinking on the subject.

"When the guidance is out, there will be opportunity for public comment and dialogue, but in the meantime we are working in this space and I think it's actually been somewhat helpful to have the discussions in some of the development programs to help inform some of the concepts that will be going into the guidance," Christl said.

Given the information void, Christl was asked at the DIA meeting whether the NOR-SWITCH trial would meet FDA's expectations for demonstrating interchangeability between a reference product and its biosimilar or whether the agency would insist upon a different study design.

NOR-SWITCH involved nearly 500 patients and was conducted by the Norwegian government. It evaluated the efficacy and safety of switching patients from Remicade to Celltrion's biosimilar version of the TNF inhibitor, compared to maintaining a control group on the reference product.

The Celltrion product, which is branded as Remsima in Europe, is approved under the proprietary name Inflectra (infliximab-dyyb) in the US. Pfizer Inc., Celltrion's commercial partner in the US, expects to launch Inflectra in late November. (Also see "How Risky Is Pfizer’s Launch Of Its Remicade Biosimilar?" - Pink Sheet, 18 Oct, 2016.)

The NOR-SWITCH results released in October showed no statistically significant difference in patient outcomes between products. (Also see "J&J Maintains Strategy For Biosimilar Remicade As Inflectra Nears" - Scrip, 18 Oct, 2016.)

The study has been hailed by biosimilar industry advocates as a significant piece of real-world evidence that switching to a biosimilar can be safely undertaken, while innovator industry groups have noted limitations to the study, including that it did not examine switching back and forth between the reference product and biosimilar. (Also see "Biosimilars Switching Debate Escalates After Remicade and Remsima Match In Landmark Study" - Pink Sheet, 20 Oct, 2016.)

… Limited To A Single Switch

The latter limitation is particularly important for FDA when it comes to interchangeability.

To demonstrate biosimilarity, FDA has asked 351(k) sponsors to provide data showing that a single transition from a reference product to a proposed biosimilar would not result in in a major risk of hypersensitivity, immunogenicity or other adverse reactions.

For example, Celltrion's BLA for Inflectra included open-label extension studies in which patients with rheumatoid arthritis and ankylosing spondylitis were either continued on the biosimilar or underwent a one-time transition from the European-approved version of Remicade to the Celltrion product.

At biosimilar advisory committee meetings, Christl and other FDA officials have tried to distinguish between data supporting a single transition necessary for biosimilar approval, and data on multiple switches that could satisfy the statutory definition for interchangeability.

However, FDA's requirement for single-transition data and its lack of formal guidance on interchangeability have created confusion among its own external experts as to what further data would be required to demonstrate interchangeability and support pharmacy-level substitution. (Also see "Biosimilar Interchangeability Requirements Pushed At Inflectra Review" - Pink Sheet, 15 Feb, 2016.)

In addition, patient advocates have raised concerns that the single-transition data will be misinterpreted by payers to justify financially driven decisions to switch patients who are stable on a reference product to a biosimilar. (Also see "Biosimilar Non-Medical Switching: Advocacy Groups, FDA Advisors Push For Action" - Pink Sheet, 14 Jul, 2016.)

"There are people right now who are just afraid of switching flat out, no matter what product, under any conditions." – Sandoz's Cohen

While NOR-SWITCH would not meet US regulatory requirements for interchangeability, Sandoz's Cohen said the study should play an important role in easing patient concerns that moving between a reference product and a biosimilar is inherently unsafe.

There have been other studies involving transitions between reference products and biosimilars, but "the NOR-SWITCH study has gotten a lot of publicity. It was sponsored by a government. I think it has legs, quite honestly," Cohen said. "It's value, I think, is going to be in public perception and acceptability across the board."

Although the NOR-SWITCH results cannot be directly extrapolated to other reference products and their biosimilars, "the concept of switching is something that people will be more willing to accept. There are people right now who are just afraid of switching flat out, no matter what product, under any conditions," Cohen said. After NOR-SWITCH, "people will say that switching is something they can be comfortable with."

Multiple Switching Studies 'From The Get-Go'

With FDA's requirements on interchangeability still unclear to the broader public, industry representatives gave their views on the types of data likely needed to support the designation.

"I think most people believe that it will involve some degree of multiple-switching studies," Cohen said. "The nature of the studies may be product-specific," depending on whether the biologic is for chronic or one-time use, as well as the half-life. "All that will impact on the nature of the switching studies themselves."

Sandoz incorporated clinical trials involving multiple switches into the development programs for its two US-approved biosimilars, Zarxio (filgrastim-sndz) and Erelzi (etanercept-szzs). (Also see "Sandoz's Multi-Switch Biosimilar Trials: A View To Interchangeability?" - Pink Sheet, 21 Jul, 2016.) The company is interested in seeking interchangeability determinations for both products but has declined to discuss its plans for doing so.

Sandoz prefers to conduct multiple-switch studies "from the get-go," Cohen said. "Now we don't have an interchangeability designation right now, but the data is there on going back and forth."

However, such studies can be challenging to design and expensive to conduct, said Celltrion Senior Advisor Stanley SeungSuh Hong.

"To be honest, it's not easy to include full clinical design to reflect for the interchangeability," he said. To incorporate multiple switches, "it's not easy, practically speaking."

Looking Beyond A Clinical Outcomes Trial

Gino Grampp, Amgen Inc.'s executive director of global operations, suggested there may be room for a more flexible approach to demonstrating interchangeability.

Amgen's first biosimilar, Amjevita (adalimumab-atto), was approved in September but may be years away from launching due to patent ligation with AbbVie Inc., which markets the reference product Humira (adalimumab). (Also see "Biosimilars: Sandoz Pegfilgrastim Review, Amgen Adalimumab Launch Extended To 2018" - Pink Sheet, 28 Oct, 2016.)

Discussing Amgen's core principles for biosimilar interchangeability, Grampp said there should be clinically relevant evidence of safe switching between a biosimilar and its reference product.

Clinically relevant evidence that switching is going to be appropriate does not necessarily mean a randomized, controlled, clinical outcomes study, Amgen's Grampp said.

"Examples of clinically relevant evidence could include the one-time transition studies that we've heard about for … some of the biosimilars developed for the US," he said. "They could include the multiple-switch studies that Sandoz has done. They could include the type of randomized, controlled, postmarket study, such as the NOR-SWITCH and other types of studies."

However, clinically relevant evidence that switching is going to be appropriate does not necessarily mean a randomized, controlled outcomes study because "clinical outcome studies are fairly insensitive," Grampp said.

"It could mean a very sensitive evaluation of immunogenicity before and after a switch, just to make sure there's no uptick in levels of binding or neutralizing antibodies or a drop in drug concentration," he said. "That would be much more sensitive than waiting five months to see if a patient has a recurrence of the disease."