Christina Corridon co-wrote this blog post with Scott Kniaz.
Back in April, we wrote a blog post covering almost everything you needed to know about the hot topic of biosimilar interchangeability—a special designation that allows pharmacies to substitute a biosimilar for a novel biologic product without the input of the prescribing provider. We also told you why it would continue to be in the news for the remainder of 2019—one reason being because the FDA promised to issue finalized guidance on interchangeability by the end of May. Well, that day has come. After releasing its draft guidance more than two years ago, and following a lengthy comment period, the FDA issued the long-awaited document on May 10th. We’ve had a chance to read it and wanted to save you some time by highlighting the most salient issues.
The finalized guidance represents the FDA’s current thinking on demonstrating the interchangeability of a biosimilar therapeutic protein product with a reference biologic, and it is intended to help biosimilar developers submit or supplement their marketing applications under the Public Health Service Act. Overall, the final guidance is consistent with the draft guidance, except in a few places. We’ve grouped our findings into three categories: 1) things the new guidance has made clearer; 2) things the new guidance has made murkier; 3) what this means for biosimilar developers.
What Is Clearer Now
The final guidance adds needed clarity around several dimensions of the switching study itself. The final guidance confirms that the clinical bar for interchangeability remains high and that the FDA expects sponsors to conduct a switching study to assess the risks associated with alternating between the reference product and the proposed interchangeable product. Specifically, the guidance clarifies issues around:
- Study design: The guidance provides illustrative examples and recommendations regarding the lead-in period with the reference product, the randomized two-arm period, the number and duration of switches, and the sample size calculation. Interestingly, the guidance also makes it clear that integrated study designs, which would simultaneously demonstrate biosimilarity and interchangeability, are acceptable as long as they are adequately powered.
- Study endpoints: The guidance stipulates that the primary endpoints of the switching study should assess the impact of alternating between the reference product and the proposed interchangeable product on clinical pharmacokinetics (PK) and pharmacodynamics (PD). These metrics are more likely to be sensitive to changes in immunogenicity or exposure due to switching. Efficacy endpoints would be secondary and supportive of the complete body of evidence and data package.
- Study population: Given the primary endpoints, the guidance recommends that the study population be adequately sensitive for detection of differences in PK, PD and immunogenicity. The guidance also clarifies that healthy subjects, or a patient population that is different from the one used for approval of the reference product, may be used, assuming there is adequate scientific justification. PK/PD considerations should determine sample sizes.
- Use of comparators not licensed in the United States: The final guidance makes it very clear that, so long as the sponsor provides adequate bridging data between the U.S. and non-U.S. comparator products, the use of non-U.S. comparator products in switching studies is acceptable. This represents a significant shift from the earlier draft guidance, where the FDA stated that the use of a non-U.S.-licensed comparator “generally would not be appropriate in a switching study.”
What Is Murkier Now
While the final guidance clarifies specific issues, it also creates ambiguities that can best be summed up by the use of the phrase “it depends.” The guidance states that several critical dimensions of the data package needed to demonstrate interchangeability are dependent on product-specific attributes. The case-by-case approach leaves sponsors to make decisions about the following:
- The need for a switching study: The final guidance states that, in the vast majority of cases, a switching study is expected for any product administered to a patient more than once. However, if a sponsor believes that data from a switching study is not necessary for the demonstration of interchangeability, the sponsor can justify its omission.
- Robustness of the data package: The guidance outlines several product-dependent factors that may impact the robustness of the data needed to support a demonstration of interchangeability. Some of these factors include structural/functional complexity (for example, the product has a single target versus multiple targets), differential immunogenicity risk profiles, and known versus unknown biological pathways. Sponsors are left to decide just how robust the data package needs to be but could fail to clear the bar by underestimating the complexity of the molecule, the mechanism of action or the disease course.
- Use of post-marketing data: The final guidance stipulates that post-marketing data alone (without data from an appropriately designed switching study) is not sufficient for a demonstration of interchangeability. However, such data can be part of the “totality of evidence” to “reduce uncertainty about interchangeability and, thus, the data needed to support a demonstration of interchangeability.” This straddling stance leaves sponsors with uncertainty about how to use real-world data and how it might help to alleviate the need for additional clinical data in their applications.
- Extrapolation: The guidance states that a sponsor may seek licensure for a proposed product in fewer “conditions of use” (aka indications) than the reference product. At the same time, the FDA recommends that sponsors seek approval for all licensed indications of the reference product whenever possible. The FDA is not requiring switching studies for all indications; rather, it requires sponsors to choose an indication for the switching study that would best support the extrapolation of data to other indications. Sponsors must then justify their choices and provide a scientific rationale for extrapolation of the data.
While the final FDA guidance creates uncertainty about the issues above, it also gives sponsors the flexibility to provide scientific justification for their choices. And sponsors are encouraged to meet with the FDA early in the application process to discuss any of these issues.
What This Means for the Industry
While the finalized FDA guidance clarifies some issues while making others more opaque, it is broadly pro-biosimilar manufacturer and pro-competition. This is in line with recent agency policymaking that supports increased market competition to drive down prices and make healthcare more affordable. The FDA’s decisions to allow the use of non-U.S. comparators, integrated studies that simultaneously demonstrate biosimilarity and interchangeability, and flexibility for sponsors to choose the indications (relative to the licensed originator) in their applications all follow this same theme. Likewise, the FDA’s focus on PK/PD endpoints (rather than efficacy endpoints) should enable a relatively shorter timeline for switching studies, with a correspondingly lower cost burden. The FDA’s “it depends” stance empowers the industry to initiate discussions with regulators early in development, take the ball and run with it. This stance will also mean increased future uncertainty around the possibility of interchangeable status attainment. For example, market incumbents—both reference companies and established biosimilar manufacturers—will need to be prepared for new biosimilar entrants to seek this status without a switching study. It will be very interesting to see how these market dynamics unfold in the future, starting with the readout of Boehringer Ingelheim’s switching study—the first of its kind—later this year. Stay tuned.