An Industry Perspective on Biosimilar Interchangeability
In a Thursday session of the SMi Biosimilars North America 2017 conference, Cindy Cao, PhD, executive director and head of United States regulatory affairs at Sandoz, looked ahead to the advent of interchangeable biosimilars.
Kelly Davio
November 17, 2017
In a Thursday session of the SMi Biosimilars North America 2017 conference, Cindy Cao, PhD, executive director and head of United States regulatory affairs at Sandoz, looked ahead to the advent of interchangeable biosimilars.
Cao opened her talk by reviewing the fact that, under the Biologics Price Competition and Innovation Act (BPCIA), a therapy seeking an FDA designation of interchangeability must first demonstrate that a product is a biosimilar, that it can be expected to produce the same clinical result as its reference in any given patient, and that it will not pose any greater risk to the patient (in terms of safety or diminished efficacy) to switch to the biosimilar rather than remaining on the originator. After a product has been granted interchangeable status, pharmacy-level substitution can take place (as governed under applicable state laws).
Disambiguating Interchangeability
Cao highlighted the fact that, while the United States defines interchangeability as a matter of federal law, the term “interchangeable” is used differently in other regulatory areas; “In the [European Union], it is not a regulatory term,” she said, but a medical one.
In the EU setting, a qualified professional who is in charge of a patient’s care may use his or her best judgement to prescribe the most appropriate therapy, whether reference or biosimilar. In the EU regulatory context, biosimilars are considered to be as safe and effective as originator therapeutics, and aren’t expected to trigger or enhance immunogenicity. Therefore, Cao explained, the products are considered medically interchangeable.
The fact that the US addresses interchangeability in legal terms can lead to misconceptions about product quality; Cao underscored the fact that the FDA does not have more than 1 standard of quality for biosimilars. An interchangeable designation simply requires additional, specific data in addition to the already “rigorous and high bar” set for FDA-approved biosimilars.
Designing the Interchangeability Study
Developers who seek to demonstrate interchangeability of their biosimilars will have to decide on the most appropriate study design for their needs, said Cao, who outlined 2 options.
First, a biosimilar developer could conduct a dedicated switching study that is intended purely to demonstrate interchangeability. Second, the developer could choose an integrated study design with a first stage intended to demonstrate biosimilarity and a second stage intended to show interchangeability in the same patient population.
For example, after a 16-week study on biosimilarity, an extension period up week 28 could be used to show interchangeability by re-randomizing patients to remain on the originator, remain on the biosimilar, or switch between the 2 therapies in order to assess pharmacokinetic and pharmacodynamic changes related to switching. Safety and immunogenicity of the therapies would be monitored throughout the entire study period.
Regardless of which design a developer selects, the study should involve a scenario in which switching is of the most clinical concern for patients, use the most sensitive patient population, assess the drug in a licensed indication, use the same route of administration as the reference biologic, and use a US-licensed reference product.
Theoretical Concerns About Switching
Cao highlighted the fact that concerns about the risks of switching biosimilars are thus far theoretical. It is important, she said, to evaluate potential risks in order to see whether any data exist to support these concerns. However, Cao said, approximately 70 studies of various designs, which have included approximately 10,000 total participants, have not showed significant declines in efficacy, increases in treatment-related adverse events, or differences in anti-drug antibodies.
Other Considerations for Interchangeable Biosimilars
Lastly, Cao addressed a key concern for biosimilar developers: how to address device design. “When [reference biologics] are close to patent expiration, usually they have an older-generation device,” said Cao. Bringing a new biosimilar to market carries the opportunity to develop a better, more patient-friendly device.
However, the need to demonstrate to the FDA a close match of the biosimilar with its reference product can make developers wary of straying far from the originator’s device design. “We need to find a better balance of how to bring a better product to the patient,” she said.
Cao opened her talk by reviewing the fact that, under the Biologics Price Competition and Innovation Act (BPCIA), a therapy seeking an FDA designation of interchangeability must first demonstrate that a product is a biosimilar, that it can be expected to produce the same clinical result as its reference in any given patient, and that it will not pose any greater risk to the patient (in terms of safety or diminished efficacy) to switch to the biosimilar rather than remaining on the originator. After a product has been granted interchangeable status, pharmacy-level substitution can take place (as governed under applicable state laws).
Disambiguating Interchangeability
Cao highlighted the fact that, while the United States defines interchangeability as a matter of federal law, the term “interchangeable” is used differently in other regulatory areas; “In the [European Union], it is not a regulatory term,” she said, but a medical one.
In the EU setting, a qualified professional who is in charge of a patient’s care may use his or her best judgement to prescribe the most appropriate therapy, whether reference or biosimilar. In the EU regulatory context, biosimilars are considered to be as safe and effective as originator therapeutics, and aren’t expected to trigger or enhance immunogenicity. Therefore, Cao explained, the products are considered medically interchangeable.
The fact that the US addresses interchangeability in legal terms can lead to misconceptions about product quality; Cao underscored the fact that the FDA does not have more than 1 standard of quality for biosimilars. An interchangeable designation simply requires additional, specific data in addition to the already “rigorous and high bar” set for FDA-approved biosimilars.
Designing the Interchangeability Study
Developers who seek to demonstrate interchangeability of their biosimilars will have to decide on the most appropriate study design for their needs, said Cao, who outlined 2 options.
First, a biosimilar developer could conduct a dedicated switching study that is intended purely to demonstrate interchangeability. Second, the developer could choose an integrated study design with a first stage intended to demonstrate biosimilarity and a second stage intended to show interchangeability in the same patient population.
For example, after a 16-week study on biosimilarity, an extension period up week 28 could be used to show interchangeability by re-randomizing patients to remain on the originator, remain on the biosimilar, or switch between the 2 therapies in order to assess pharmacokinetic and pharmacodynamic changes related to switching. Safety and immunogenicity of the therapies would be monitored throughout the entire study period.
Regardless of which design a developer selects, the study should involve a scenario in which switching is of the most clinical concern for patients, use the most sensitive patient population, assess the drug in a licensed indication, use the same route of administration as the reference biologic, and use a US-licensed reference product.
Theoretical Concerns About Switching
Cao highlighted the fact that concerns about the risks of switching biosimilars are thus far theoretical. It is important, she said, to evaluate potential risks in order to see whether any data exist to support these concerns. However, Cao said, approximately 70 studies of various designs, which have included approximately 10,000 total participants, have not showed significant declines in efficacy, increases in treatment-related adverse events, or differences in anti-drug antibodies.
Other Considerations for Interchangeable Biosimilars
Lastly, Cao addressed a key concern for biosimilar developers: how to address device design. “When [reference biologics] are close to patent expiration, usually they have an older-generation device,” said Cao. Bringing a new biosimilar to market carries the opportunity to develop a better, more patient-friendly device.
However, the need to demonstrate to the FDA a close match of the biosimilar with its reference product can make developers wary of straying far from the originator’s device design. “We need to find a better balance of how to bring a better product to the patient,” she said.
