The US Food and Drug Administration (FDA) recently completed a flurry of activity to help define the biosimilar pathway, including issuing final guidances on biosimilar clinical pharmacology and biologics non-proprietary naming, as well as a draft guidance on biosimilar interchangeability. In parallel, litigation that should clarify the BPCIA patent resolution process, including timing of the biosimilar applicant’s notice of commercial marketing is proceeding through the Supreme Court.

Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (December 2016): With this guidance, FDA finalizes the previous draft guidance of the same title. The final guidance largely tracks the previous draft. Of note, the final guidance removes categories of “similarity” (see previous post) in favor of describing certainty about similarity derived from analytical data on a development-phase continuum. This change is consistent with the statutory requirement that a biosimilar must be “highly similar” to the reference product.

Guidance for Industry: Nonproprietary Naming of Biological Products (January 2017): The final version of this guidance maintains the FDA position in the draft guidance that all biological products should carry distinguishable non-proprietary names. Specifically, related biologics and biosimilars should share a common core name, which should be followed by a dash and a four letter nonsense suffix. The core names are anticipated to be United State Adopted Names (USAN) for the biological substance. For example, the guidance provides a made-up example, replicamab-cznm and replicamab-hjxf, for two different products containing a version of the replicamab biological substance. Sponsors of new biological products should submit up to 10 proposed suffixes to the core name as early as the IND stage of development. Sponsors of marketed products should submit the suffix name change as a prior approval supplement.

Draft Guidance for Industry: Considerations in Demonstrating Interchangeability With a Reference Product (January 2017) (Draft Interchangeability Guidance): Perhaps the most anticipated biosimilars guidance since the enactment of the BPCIA, the Draft Interchangeability Guidance addresses general principles, product specific factors, the type and amount of data and other information, appropriate use of approved products in comparative studies, post-marketing studies, and product presentation (i.e., packaging and delivery devices) for demonstrating interchangeability to a reference biological product.

The Draft Interchangeability Guidance does not anticipate immediate situations where an interchangeable biologic may be approved without clinical studies. However, the clinical studies for products intended to be used more than once (i.e., switching studies) may use different endpoints than those used to demonstrate biosimilarity, and PK/PD endpoints rather than clinical endpoints are recommended. In general, the switching studies should be conducted in patients, not in healthy volunteers, and extrapolation of indications with appropriate scientific justification will be permitted for interchangeable biologics as it is for biosimilars. FDA recommends studies that evaluate changes in treatment involving two or more switches (alternating intervals) with the proposed interchangeable biologic and the reference product. The US-approved reference product should be used for studies to support interchangeability.

Because the interchangeable product may be substituted without the knowledge of the prescriber, FDA is concerned that patients and care-givers will be able to appropriately use the proposed product. Sponsors are instructed to conduct threshold analyses to determine if there are any minor or major differences in design between the reference and proposed interchangeable product, which will determine the need for additional data and information, such as human factors studies, to support a demonstration of interchangeability. Interoperability is not required, but differences should not negatively affect the end-user’s ability to deliver the biological product. In an appendix, FDA provides additional advice on comparative human factor study design and analysis.

Finally, the Supreme Court is preparing to hear arguments on April 26, 2017 regarding the BPCIA patent resolution process, including the notice of commercial marketing requirement. The case, Sandoz Inc. v. Amgen Inc., Docket no. 15-1039, involves the operation of two notification provisions in the BPCIA. Under the BPCIA, a biosimilar applicant is directed to provide a reference product sponsor (RPS) with a copy of its marketing application no later than 20 days after FDA notifies the applicant that its application has been accepted for review. 42 USC 262(l)(2). This provision is designed to permit the RPS to respond, within 60 days, with a statement asserting any patents that will be infringed by the application, and then a series of steps to resolve infringement disputes, culminating with a right to bring an infringement suit. 42 USC 262(l)(3)-(6). The Federal Circuit concluded that the biosimilar applicant may choose not to provide a copy of its application, and the only remedy available to the RPS is to seek a claim of patent infringement. The Supreme Court will now consider whether this notification is, in fact, optional. Second, the BPCIA directs that a biosimilar applicant “shall provide notice to the [RPS] not later than 180 days before the date of the first commercial marketing” of the licensed biosimilar product. 42 USC 262(l)(8). The Federal Circuit held that the biosimilar applicant cannot give the required notice until FDA has approved the biosimilar application. The Supreme Court will consider whether the biosimilar applicant may give the notice during the pendency of its application so that it may begin marketing at the time that its application is approved instead of having to wait for six months after approval. The US Solicitor General has weighed in and opined that the Federal Circuit was correct to view the only remedy for failure to disclose the marketing application to be declaratory relief, but that the Federal Circuit should be reversed on the timing of notice to the RPS, which may be given prior to approval of the application. A decision in the case is expected before the end of June, and the Supreme Court’s ruling on both issues is expected to have profound effects for biosimilar development.