In our recent blog, “Interchangeability in Biosimilars: Implications for Biosimilar Drug Development and Clinical Trials,” we reviewed the implications an interchangeable label might have on biosimilar development and usage. Since this publication, the U.S. Food & Drug Administration (FDA) has released a draft guidance titled “Considerations in Demonstrating Interchangeability With a Reference Product,” which provides recommendations for the standard that will be expected of an interchangeable biosimilar product. Herein, we will look at the highlights of the guidance and what it means for clinical trial design in programs seeking an interchangeable label.
An interchangeable label for a biosimilar product will mean that it may be substituted for a reference product without involvement from the proscribing healthcare provider. In the United States this is commonly called pharmacy-level substation. The ability for pharmacies to substitute an FDA-approved interchangeable product is regulated at the state level and currently 25 states have already passed legislation regarding biosimilar interchangeability.
Biosimilar Interchangeability= Switching studies
In the draft guidance, the FDA references three points of emphasis the data within an interchangeable application should seek to satisfy:
- “is biosimilar to the reference product”
- “can be expected to produce the same clinical result as the reference product in any given patient”
- “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 address these points the FDA “expects that applications generally will include data from a switching study or studies in one or more appropriate conditions of use,” for which the biosimilar will be used as a substitute for reference product (this will be looked at in more detail below). Switching studies will be especially important when the product is expected to be administered more than once. These switching studies are intended to evaluate any risk in safety, immunogenicity, or efficacy involved with alternating or switching between the applicant interchangeable and the reference product.
It is recommended that following a lead-in period of treatment with the reference product, a randomized two-arm switching period should occur. In one arm, switching between the proposed interchangeable product and the reference product (switching arm) will be tested and the other (non-switching) arm will continue to receive only the reference product. Ideally the FDA proposes that switching studies should evaluate changes in treatment that result from two or more alternating exposures (switch intervals). From these studies, it is expected that study endpoints should primarily focus on clinical pharmacokinetics, pharmacodynamics, immunogenicity, and safety. It is also strongly recommended that these studies are conducted in patients to most closely replicate how the interchangeable product will be used in clinical practice.
Of note, beyond the efficacy and safety of the product itself, the FDA will also expect that the interchangeable product has a similar user interface as the reference product. Examples provided include presentations, container closure system, and delivery devices when applicable.
FDA example of presentation: “if the reference product is only marketed in a vial and a prefilled syringe, a sponsor should not seek licensure for the proposed interchangeable product for a different presentation, such as an auto-injector.”
It’s a Whole New Ballgame in Clinical Trial Design
Release of the guideline now provides a template by which sponsors within the United States can begin perusing interchangeable designation in biosimilar drug development trials. However, three major clinical trial implications arise from the agency’s draft document: the selection of the reference product; the mosaic of indications for which interchangeability is sought; method by which the interchangeable is presented for clinical use (i.e., route, dosage, device).
With regard to a reference product, the FDA strongly recommends a U.S.-licensed product be used as the reference in any interchangeability study design. As an example, GP2015 (Erelzi®), being evaluated for treatment of rheumatoid arthritis, is one drug that may already face this challenge. GP2015 is being tested in an ongoing switching study with European Union approved Enbrel® as the reference product. Therefore, based on the guidance this product may face difficulty qualifying for an interchangeable label in the United States.
Another possible challenge for biosimilar clinical trials may be providing evidence that the proposed interchangeable can be applied across all the indications of the reference product. The FDA noted that it recognized some sponsor may seek licensure for a proposed interchangeable product for fewer than all conditions of use for which the reference product is licensed. However, the guidance recommends sponsors do seek licensure in all conditions of use as the reference product when possible. This is further established in the guidance by the following statement:
“FDA expects that sponsors will submit data and information to support a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in all of the reference product’s licensed conditions of use.”
As noted above, this will mean sponsors must complete one or more switching studies. The extent and number of studies will vary from product to product depending on the complexity of the product and the depth of the analytical data supporting it. In addition, the FDA guidance does allow for extrapolation of data to support interchangeability across reference product indications. Here trial designers will need to carefully determine which data points will be needed to provide sufficient scientific evidence for extrapolation and what conditions will allow for collection of these data. At the end of the day the “totality” of the data must support the conclusion that the proposed interchangeable can be expected to produce the same clinical result as the reference product in any given patient. Clinical trial designers and sponsors will have to actively engage the FDA to determine the objectives and number of switching studies that will be required for a proposed interchangeable.
Finally, studies will also have to be carefully planned to ensure that every aspect of each arm matches (i.e., dosing route, schedule, devices), because as noted above interchangeability will be evaluated not only be efficacy, but also at the level of patient interface.
Will Biosimilar Development Sponsors Seek Interchangeability?
With increased standards for interchangeability and potentially lengthened timelines to complete required studies, many biosimilar manufactures may chose not to seek an interchangeable label. This is also placed against the observation that interchangeability may not be required for commercial competitiveness, as some 2017 formularies have opted for biosimilar products instead of originator brands, thus obviating the potential benefit from an interchangeability claim. Together the increased standards and potential lack of increased value may mean that many sponsors forgo seeking interchangeability. For those that do pursue an interchangeable label, well thought out, strategic trial design and execution will be imperative for successful navigation from approval to commercialization.
Worldwide Clinical Trials (Worldwide) has experience in the complex challenges associated with meeting regulatory requirements, and positioning for commercial success. As a result, Worldwide looks forward to working with sponsors to address the challenges facing interchangeability approval, with strategic, innovative, and efficient clinical trial design.