Sandoz, with its filgrastim biosimilar (Zarxio) having been the first biosimilar to gain FDA approval and to launch in the US market, has had extensive experience in the biosimilars space. Carlos Sattler, MD, head of clinical development and medical affairs at Sandoz, recently spoke with The Center for Biosimilars® about both the biosimilar development process and the regulatory landscape that lies ahead.
Sandoz, with its filgrastim biosimilar (Zarxio) having been the first biosimilar to gain FDA approval and to launch in the US market, has had extensive experience in the biosimilars space. Carlos Sattler, MD, head of clinical development and medical affairs at Sandoz, recently spoke with The Center for Biosimilars® about both the biosimilar development process and about the regulatory landscape that lies ahead.
When asked about considerations that developers must bear in mind when they design clinical trials for biosimilar products, Sattler emphasized that the goal of the phase 3 study is to address any residual uncertainties about the similarity of the proposed biosimilar and its reference, not to demonstrate safety and efficacy of the therapy itself. As such, the phase 3 study for a biosimilar may differ in multiple ways from the phase 3 trial that supported the reference product’s approval. The chosen indication and population for the trial may be different, and the chosen endpoint for the study may also be different; all of these will be selected on the basis of their ability to detect potential differences in safety or efficacy.
However, while the phase 3 study is traditionally the last step in the development program that includes analytical as well as pharmacokinetic (PK) and pharmacodynamic (PD) data, Sattler noted that, in specific circumstances, it may be feasible to forego a phase 3 confirmatory safety and efficacy study for the proposed biosimilar in comparison with its reference. “If the analytics are such that they demonstrate high similarity, then the FDA may only require a PK/PD demonstration,” he explained, and the same authority to waive a phase 3 study exists for the European Medicines Agency (EMA).
While the feasibility of a phase 3 study waiver would depend upon the scenario, this approach might be especially suited to less complex biologics, “or it may occur as our analytics improve, and there’s been a tremendous improvement in the sensitivity and breadth and scope of our analytical tools,” he said.
However, he acknowledged, education for stakeholders would be key in the case of such a waiver. Patients and physicians would need to understand that all of the necessary regulatory steps had been taken by the FDA or EMA to ensure that the efficacy and safety of the biosimilar versus its reference were not in question. “There may be some concern because the biosimilar paradigm concept and design is still relatively new, so a lot of education has to occur. Even though there may be concerns, I think a lot of this could be handled through education,” he said.
While waivers of phase 3 studies may not be a regulatory reality yet, Sattler, like many stakeholders, is looking ahead toward one particular regulatory development that is relatively near on the horizon: the FDA’s long-awaited finalization of its guidance on demonstrating interchangeability of biologic products.
Sattler says he hopes to see several features of the current draft guidance addressed in revised guidance, and among his concerns is the draft guidance’s call to use PK endpoints as a way to measure potential immunogenicity of a proposed interchangeable biologic.
“There are several issues with PK endpoints as required by the interchangeability guidance that was initially published,” Sattler said. “First of all, a PK design [of this type] would result in a much longer study than a typical PK study. Remember that these would be PK studies in patients, therefore recruitment and retention could be an issue” because of the intensive blood sampling that would be required, he explained, and a large number of study sites would be necessary. Furthermore, one downside of using PK to measure potential immunogenicity is that there are factors independent of immunogenicity that can impact PK, such as patients’ underlying disease.
A second issue he hopes to see addressed is the requirement to use US-licensed reference products for comparison with proposed interchangeable biosimilars. “The stated concern is that there may be differences between the US reference and the ex-US reference, but I think that goes against the concept of using highly advanced analytical techniques” that allow developers to show the similarity between US and non-US products.
Also of concern for Sattler is the FDA’s statement in the draft guidance that comparative use human factor studies may be needed in order to assess whether differences in product presentation could prevent licensure of a product as interchangeable. According to the draft guidance, the objective of these studies is to assess any differences in the use error rate between the reference and the proposed interchangeable, and this, says Sattler, poses a challenge. “They’re requesting that the results be subject to statistical analysis to establish an error rate for both the reference product and the biosimilar in these human use studies. The requirement of statistical analysis is a concern because human factor studies are designed to identify and evaluate the use of the device, but not to establish an error rate, so this would be a particularly novel requirement.”
Finally, Sattler said, he has concerns about the potential FDA requirement for the provision of post-marketing data describing the real-world use of a biosimilar—including safety data related to switching—to address residual uncertainty about interchangeability.
Sattler explained that, in order to provide a robust body of post-marketing data for this purpose, a product would have to have market uptake before it could even be considered for an interchangeable designation. And importantly, he noted, more than a decade of experience with biosimilars in Europe has not resulted in a post-marketing surveillance effort that characterized significant differences between a biosimilar and its reference.
Sattler emphasized, however, that Sandoz believes that “whether an approved biosimilar is designated as interchangeable or not, the risk posed by switching between the biosimilar and the reference medicine is no greater than the risk posed by using the reference medicine only.”