We are on the verge of a few eagerly awaited decisions by the Food and Drug Administration (FDA). Celltrion and its partner Pfizer expect to hear news on their trastuzumab biosimilar in April, as does Celltrion separately on its rituximab biosimilar. These should make a significant impact on the evolution of biosimilars in the US and on marketshare penetration, but the FDA’s decision around the fourth filgrastim agent from a lesser- known player could be even more important to the industry.

One of the critical areas that differentiate 351(k) from 351(a) biologic licensing applications (BLAs) is that the FDA has emphasized the primary importance of evidence supporting the pharmacokinetic, pharmacodynamic, and structural similarity of the biosimilar to the originator product. In comparison, the standard BLA requires a sufficient catalog of data from phase 1, 2, and 3 clinical trials that point to the efficacy and safety of the biologic. To many in the biosimilar field, the inverted pyramid illustration left is very familiar.

To date, the biosimilars brought to the application or registration process have been evaluated on their physiochemical characterization as well as the results of phase 2 and/or 3 clinical trials in at least one target indication. This is where it becomes interesting: Adello Biologic’s 351(k) application for filgrastim comprises the physiochemical biosimilarity evidence, but in terms of clinical data, only phase 1 studies were performed. That is, these studies included healthy volunteers only. And the studies further demonstrated the comparable pharmacokinetics and pharmacodynamics of this biosimilar and Neupogen^®, the originator G-CSF drug.

This decision was not made in a vacuum. The manufacturer consulted with the FDA, as all prospective biosimilar makers do, on the requirements of their data packages. And the FDA accepted the application in September 2017. This fits with the agency’s policy to place ever-increasing weight on the physiochemical data as part of its “totality of evidence” approach. In its 2015 guidance, the FDA stated, “As a scientific matter, a comparative clinical study will be necessary to support a demonstration of biosimilarity if there is residual uncertainty about whether there are clinically meaningful differences between the proposed product and the reference product based on structural and functional characterization, animal testing, human [pharmacokinetic and pharmacodynamic] data, and clinical immunogenicity assessment.” With Adello’s filgrastim, one assumes that the FDA made the decision that the studies in healthy volunteers was sufficient.

Since Adello would be the second filgrastim biosimilar approved (also the fourth filgrastim on the market), the FDA may decide to dispense with an Advisory Committee meeting to discuss publicly the merits and issues with the agent. However, because this could be the first biosimilar approved without phase 2 or 3 clinical data, the FDA may decide on a conservative course, allowing the clinical community and the public to weigh in.

One could see how the lack of clinical data in actual patients will give pause in an Advisory Committee session. A patient undergoing cancer chemotherapy will likely have a different immunologic status, it can be argued, which may result in immunogenicity problems in real-world use. For agents already marketed in Europe, such issues may be absent and can be considered as part of the totality of evidence. Adello, however, does not market their biosimilar elsewhere.

Even if the Advisory Committee does not recommend (or a slight majority recommends) approval, the FDA could decide to license the drug anyway, in view of its stated policy to get biosimilars to market more rapidly. If this is the case, it would help ensure that R&D costs remain as low as possible for prospective biosimilar manufacturers, without the requirement of performing expensive phase 2 or 3 trials.

The question of whether an Advisory Committee will be held is still unknown. In response to queries, an FDA spokesman offered that the agency had “previously articulated a general expectation that a proposed biosimilar to a given reference product would be discussed at an Advisory Committee meeting if a proposed biosimilar to that reference product had not previously been discussed at an AC meeting. Subsequent proposed biosimilars to a given reference product may also be discussed at an AC meeting if FDA determines that there are specific issues to discuss.” In other words, no one knows. A query to Adello was not answered as of the publication of this article. Any updates will be noted in this space.