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Emerging Key Concepts in Biosimilar Development

March 8, 2017 | Kathryn Tworkoski, PhD, Clinical Research Scientist II | Regulatory Affairs, Drug Development Consulting

Biosimilars are a relatively new class of therapeutics. To date, only 4 biosimilars have been approved by the FDA (ZARXIO™, INFLECTRA®, ERELZI™, and AMJEVITA®); 3 of those 4 approvals occurred within the past year, and all 4 approvals occurred within the past 2 years! In this post, we’re going to take a quick look at the FDA’s current thoughts on biosimilar development, as well as a few key concepts in the field.

What do we mean by “biosimilar?”

The FDA approval pathway for biosimilar products (known as the 351[k] pathway) was formally established in a 2009 amendment to the Public Health Service Act called the Biologics Price Competition and Innovation Act (BPCIA). But before looking at biosimilars, it is important to understand a key difference between drugs and biologics. Namely, drugs generally have known chemical structures, while biologics are complex products that are not easily characterized.

Consequently, biosimilars should not be confused with generic drugs; while generic drugs are required to have the same active ingredient as their reference product, biosimilars are biologic products that need to be highly similar to their biologic reference product. To approve a biosimilar, the FDA must determine that the product is “highly similar to the reference product” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”

Ok, so how is a product determined to be biosimilar?

To facilitate understanding of the concept of biosimilarity, the FDA released a final December 2016 guidance titled “Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product.” In the guidance, the FDA focuses on 3 key concepts that are used to compare a biosimilar and its reference product: PK/PD response, analytical quality and similarity, and residual uncertainty.

Image courtesy of Digitalart
at Freedigitalphotos.net

A biosimilar’s PK properties (how the drug is affected by the body) and PD properties (how the body is affected by the drug) are used to measure its clinical response in comparison to a reference product.

The FDA states that broad panels of PD biomarkers “that capture multiple pharmacological effects” may add value to studies. Additionally, derived PK parameters are recommended to assess similarity when PD biomarkers cannot be used to detect clinically meaningful differences.

The analytical qualities of a biosimilar are compared to the chemistry, manufacturing, and controls (CMC) of a reference product. In a 2014 draft guidance, the FDA stated that biosimilar products could broadly fall into 1 of 4 analytical categories (see below). These categories, however, were generally seen as imprecise, and there was a call for additional clarification. Consequently, the FDA tweaked the categories used in the final 2016 guidance, as shown below.

As you might expect, there are some questions as to how fingerprint-like similarity may be achieved. In the final guidance, Sponsors are encouraged to compare products using a “fingerprint‑like analysis algorithm that covers a large number of product attributes and their combinations with high sensitivity using orthogonal methods.” Ultimately, the take home message seems to be that the FDA still allows significant room for interpretation within these terms, and it is likely that additional clarification will be required on an individual basis.

At this point, we’ve mentioned residual uncertainty a few times. Simply put, residual uncertainty refers to any aspects of a biosimilar that are not deemed similar to the reference product (PK, PD, analytical qualities, etc). The FDA evaluates residual uncertainty using a risk‑based approach and offers several tips within the guidance for managing uncertainty.

What is interchangeability, anyway?

One of the key aspects of a biosimilar product is whether or not it is interchangeable with the reference product. As you might expect, an interchangeable product is both biosimilar and “expected to produce the same clinical effect as the reference product in any given patient.” To further describe this concept, the FDA released a January 2017 draft guidance called “Considerations in Demonstrating Interchangeability with a Reference Product.”

The draft guidance focuses on the data needed to support interchangeability and the design and/or analysis of related clinical trials. The FDA states that data needed to demonstrate interchangeability are linked to the quality of the available data demonstrating biosimilarity. That is, biosimilar products with less residual uncertainty may require less additional data to support interchangeability.

Of note, although the FDA states that observational data from a postmarket setting can bolster a claim of interchangeability, these data are generally not sufficient in and of themselves to establish a claim of interchangeability. Instead, separate switching studies are likely to be required.

Switching studies involve exchanging the study medication with the reference product to verify that the exchange does not increase “risk in terms of safety or diminished efficacy.” For products that are only administered once, a switching study may not be needed. For other study types, the FDA offers insight on the design of switching studies, the selection of appropriate reference products, and the conditions under which data may be extrapolated to support a given indication.

What else should I know about biosimilars?

As new guidances shape biosimilar studies and 351(k) applications, there is a corresponding need to sort out the business-related implications of biosimilars.

A very practical example can be found in the January 2017 draft guidance titled ”Nonproprietary Naming of Biological Products.” In it, the FDA proposes a new naming convention that will be applied both prospectively and retrospectively. Specifically, a common core nonproprietary name will be used consistently across related biological products, while unique suffixes will designate individual products.

For example, the approved product INFLECTRA® is a biosimilar of the reference product REMICADE® (nonproprietary name: infliximab). The established nonproprietary name for INFLECTRA® is infliximab-dyyb, indicating that it is an infliximab product but not exactly the same as infliximab. If additional biosimilars to REMICADE are approved in the future, their nonproprietary names will be infliximab-xxxx, where xxxx represents a unique four letter suffix. If you want a more detailed explanation of why 4 letters are used and how they are selected, take a look at the guidance!

Image courtesy of Kittisak
at Freedigitalphotos.net

A more complex issue, and one that it still being litigated in the courts, concerns when a biosimilar can legally be placed on the market following FDA approval. The BPCIA states that a biosimilar company is required to inform the reference product company of the impending release of the biosimilar at least 180 days before the biosimilar product is launched. There is, however, some question as to when that 180-day notice can be given.

In 2014, Amgen (the innovator company) sued Sandoz (the biosimilar company, a Novartis unit) for alleged patent infringement after Sandoz launched the biosimilar ZARXIO™. Sandoz had provided notice to Amgen that it intended to market a biosimilar version of Amgen’s NEUPOGEN® upon approval of the BLA. However, Amgen argued that based on the wording of the BPCIA, the 180-day notice could not be given until after the biosimilar was actually approved by the FDA.

Initially, a district court ruled that the 180-day notice could be given before biosimilar approval, but a federal appeals court subsequently decided that a biosimilar must be approved before the 180-day notice could be given. Several companies, however, feel that this practice unfairly delays the development of biosimilars. Novartis is currently challenging the ruling, and the case is expected to go before the Supreme Court this spring.

There’s still a lot to work out!

These issues are especially important because although the US biosimilar field is currently small, it’s expected to expand dramatically. Novartis alone is hoping to launch 5 biosimilars by 2020. And as the number of biosimilar applications and approvals increase, the way in which biosimilars are developed, approved, and marketed will continue to evolve (for a description of formal FDA biosimilar meetings, see our previous blog post).

If you have any questions about biosimilar products, just let us know; we’re happy to help!

Category: Regulatory Affairs, Drug Development Consulting
Keywords: Biosimilars, 351(k), interchangeability

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