Patrice P. Jean, Ph.D.
Thomas F. Lavery IV

Sandoz’s filgrastim could be a good test case as the company seeks FDA approval under the 351(k) abbreviated pathway.

The era of biosimilars has finally arrived. On July 24, 2014, over four years after the enactment of the Biologics Price Competition and Innovation Act, the FDA has approved for review the first biosimilar application, an application from Sandoz for a biosimilar of Amgen’s filgrastim sold as Neupogen®. Filgrastim is a pharmaceutical analog of human granulocyte colony stimulating factor that is used to treat neutropenia, a condition where the body does not make enough neutrophils, a type of white blood cell.

Sandoz already has marketed biosimilars of filgrastim in more than 40 foreign countries. And in the United States, Teva has received approval, under the 351(a) pathway for novel biologics, to market a version called tbo-filgrastim. The novelty here is that Sandoz is seeking approval under the 351(k) abbreviated pathway for biosimilars. The industry is wondering whether this pathway will provide enough of an advantage over the pathway for novel biologics to make it worthwhile. This in turn will depend on the criteria for (1) biosimilarity, (2) indication extrapolation, and (3) interchangeability. The FDA’s review of Sandoz’s application will likely shed light on these criteria—and may determine the viability of this pathway. 

Filgrastim Is a Good Test Case

Sandoz’s filgrastim is a good test case. Having only 175 amino acids and no glycosylation, filgrastim is a simple molecule—the FDA has described it as relatively small and easy to characterize.1 Sandoz has already demonstrated in publications that is has, through state-of-the-art methods, thoroughly characterized this molecule.2 Further, Sandoz’s filgrastim has approval in several foreign countries and presumably years of post-marketing surveillance data. Thus, with Sandoz’s application, the FDA can focus less on the scientific details of the biosimilar and more on the implementation of the pathway.

Demonstrating That a Product Is Biosimilar to Its Reference Product

To demonstrate biosimilarity, a sponsor must provide sufficient data and information to show (1) that the proposed biosimilar and its reference product are highly similar despite minor differences in clinically inactive components and (2) that there are no clinically meaningful differences between the products as to safety, purity, and potency.3 The foundation of that demonstration is the analytical comparisons of the two molecules. In recent guidance, the FDA identified a four-tiered scheme for assessing the analytical differences between a proposed biosimilar and its reference product. According to the guidance, a biosimilar applicant’s comparative analytical studies “may lead to one of four assessments”: not similar, similar, highly similar, and highly similar with fingerprint-like similarity.4

Stakeholders have complained that these categories are vague and that it is unclear how these tiers will be used in the FDA’s review process. Some stakeholders have also criticized the guidance’s suggestion that an applicant can overcome analytical differences between a biosimilar and its reference product through clinical studies. Other stakeholders have objected to the guidance’s suggestion that biosimilar applicants may defer clinical evaluation of safety and immunogenicity until after approval of their biosimilars. Having Sandoz’s biosimilar application should help the FDA clarify what is required to show that a biosimilar is “highly similar” to its reference product.

Indication Extrapolation

Given that the clinical performance of the reference product has been established, the nonclinical and clinical studies required for approval of a biosimilar may be reduced compared with the studies required for approval of the reference product. Developing a biosimilar is made even more appealing by the possibility of approval for all indications held by the reference product based on less extensive nonclinical data and minimal clinical data in only a subset of indications. Sandoz has explained that a big reason for developing a biosimilar under the 351(k) pathway, as opposed to the novel biologics pathway, is indication extrapolation.5 Sandoz contends that, without this shortcut, developing a biosimilar would be prohibitively expensive, as a clinical trial for each indication can cost $100 million.6

Sandoz is seeking approval for all five of Neupogen’s indications through extrapolation. To obtain approval for each of these extrapolations, Sandoz has to show “sufficient scientific justification.” The FDA has not issued much guidance on what that entails. How the FDA moves forward with extrapolation is important because the effort to achieve multiple indications can increase the development cost of a biosimilar and thus the price of the product to the patient. Although the FDA has not issued detailed guidance on extrapolation, it is likely that the FDA will approve extrapolation to all five indications because filgrastim has a single binding site and mechanism of action and because the European Medical Agency, which has similar regulatory considerations for extrapolation, has approved extrapolation to all five indications.7


In addition to indication extrapolation, interchangeability is another reason why a biosimilar sponsor would file an application under the abbreviated 351(k) pathway rather than the novel biologics pathway. The advantage of interchangeability is that the biosimilar may be substituted for the reference product without consent from the prescribing healthcare provider, making it easier for the biosimilar to penetrate the market.

The FDA can designate a biosimilar as an interchangeable biologic when the following criteria are met: (1) The biosimilar can be expected to produce the same clinical result as the reference product in any given patient and (2) the ability of two products to be exchanged with each other without a significant risk of an adverse health outcome.

The FDA has offered little FDA guidance on how a biosimilar can meet these criteria. It has stated that while applicants may file a 351(k) biosimilar application and request the interchangeable designation, it will postpone consideration of interchangeability until the biosimilar has been approved and there has been some market experience. The FDA plans to issue a guidance document on this issue later this year8 that will explain how it will determine whether a biosimilar is interchangeable.

Will Sandoz seek an interchangeability designation for its filgrastim biosimilar? The foreign clinical trials that Sandoz has run indicate that Sandoz may do so: Sandoz conducted a Phase III trial in Europe, where the efficacy of its proposed product was compared to the reference product and included switching patients between treatments to try to address issues of interchangeability.9


For the biosimilar pathway to succeed, the FDA will need to clarify its review process, and potential applicants will need to see, through real-world examples, the advantages of the pathway: the development shortcuts, such as minimal clinical data and indication extrapolation, and the ability to obtain an interchangeability designation. The pharmaceutical industry is watching to see whether Sandoz’s filgrastim will serve as that initial example. Under the Biosimilar User Fee Act, the FDA has set a goal for reviewing applications within 10 months of receipt. So by March 15, 2015—10 months after Sandoz submitted its application—the industry will have its first indication as to whether the era of biosimilars will be successful or not. 

Patrice P. Jean, Ph.D. ([email protected]), is a partner and Thomas F. Lavery IV  ([email protected]) is an associate at Kenyon & Kenyon LLP. 

1 Baghdadi, “Biosimilars in 2014: An Interview with FDA New Drugs Head John Jenkins.” The RPM Report. March 4, 2014.
2  McCamish et al., “The State of the Art in the Development of Biosimilars.” Clinical Pharmacology & Therapeutics, Vol. 91(3), pp. 405–417. 2012.
3  42 U.S.C. § 262(i)(2).
4  “Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product,” 79 Fed. Reg. 27622. May 14, 2014.
5  Sandburg, “Waiting for Biosimilars: From Manufacturing to Litigation, Stakeholders Prepare for U.S. Market,” The Pink Sheet. June 16, 2014.
6 Id.
7  Barosi et al., “Key Concepts and Critical Issues on Epoetin and Filgrastim Biosimilars,” Haematologica, Vol. 96(7), pp. 937–942. 2011.
8  “Guidance Agenda: New & Revised Draft Guidances CDER Is Planning to Publish During Calendar Year 2014,” available at
9  Sutter, “Sandoz’s Biosimilar Filing Is Culmination of Paradigm Shift in FDA Drug Review,” The Pink Sheet. July 28, 2014.

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