Development and Approval of Biosimilar Products

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Leah Christl, PhD

Albert Deisseroth, MD, PhD

Richard Pazdur, MD

There is no single study that will demonstrate biosimilarity. That is why FDA recommends a stepwise approach to data generation and evaluation of residual uncertainty at each step.

—Leah Christl, PhD

INSIDE THE BLACK BOX is an occasional column providing insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, Leah Christl, PhD, and Albert Deisseroth, MD, PhD, answer questions about biosimilar products. Dr. Christl is the Associate Director for Therapeutic Biologics and the team leader for the Office of New Drugs’ Therapeutic Biologics and Biosimilars Team in the Center for Drug Evaluation and Research. Dr. Deisseroth is a team leader in the Division of Hematologic Products.


The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of health reform (the Affordable Care Act) and was signed into law on March 23, 2010. The BPCI Act created an abbreviated licensure pathway for biologic products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. The ASCO Post spoke with Drs. Christl and ­Deisseroth about biosimilars and the BPCI Act.

Understanding Biosimilars

First, can you tell us what a biosimilar product is?

Dr. Christl: To understand biosimilar products, it is important first to understand how biologic products are defined and regulated. Many of today’s important medications are biologic products, generally derived from a living organism. This material can come from many sources, including humans, animals, microorganisms, or yeast. Biologic products are licensed under the Public Health Service Act (PHS Act), unlike drugs that are approved under the Food, Drug, and Cosmetic Act (FD&C Act).

In addition to creating an abbreviated pathway for licensure of biosimilar biologic products, the BPCI Act revised the definition of “biologic product” to include proteins, except for chemically synthesized polypeptides. The term “biologic product” is defined under the PHS Act as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product … applicable to the prevention, treatment, or cure of a disease or condition of human beings.…” Historically, some proteins, such as human growth hormone, have been approved as drugs under the FD&C Act, whereas other proteins, such as blood factors, have been licensed as biologics under the PHS Act.

A biosimilar is a biologic product that is highly similar to an FDA-licensed reference product, notwithstanding minor differences in clinically inactive components, and has no clinically meaningful differences in terms of safety, purity, and potency (ie, safety and effectiveness) from the reference product. The term “reference product” here refers to the single biologic product licensed under the PHS Act against which a biosimilar is evaluated. A biosimilar product can only be licensed if it has the same mechanism(s) of action, route of administration, dosage form, and strength as the reference biologic product and only for the indications and condition(s) of use that have been approved for the reference biologic product.


What is the abbreviated license pathway for biologic products?

Dr. Christl: A biologic product that is demonstrated to be “biosimilar” to the reference product may rely for licensure on, among other things, publicly available information regarding FDA’s previous determination that the reference product is safe, pure, and potent. This licensure pathway under section 351(k) of the PHS Act permits a biosimilar biologic product to be licensed based on less than a full complement of product-specific preclinical and clinical data. 


Can you clarify the differences between “stand-alone” and biosimilar product development?

Dr. Christl: As previously noted, the reference product is the single biologic product licensed under the PHS Act against which a biosimilar is evaluated. The reference product is licensed by FDA under section 351(a) of the PHS Act based on a full complement of product-specific preclinical and clinical data. The reference product can be considered a “stand-alone” application.

The goal of “stand-alone” development is to independently demonstrate that the product is safe and effective for the intended conditions of use, and drug development starts with preclinical research and progresses through phase I, II, and III trials. The goal of biosimilar development is to demonstrate biosimilarity between the proposed product and a reference product and not to independently establish the safety and effectiveness of the proposed product. 


What is required to demonstrate ­biosimilarity?

Dr. Christl: The PHS Act requires that a 351(k) application include information demonstrating biosimilarity based upon data derived from (1) analytic studies demonstrating that the biologic product is “highly similar” to the reference product, notwithstanding minor differences in clinically inactive components; (2) animal studies (including the assessment of toxicity); and (3) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product. FDA may determine, in its discretion, that an element described above is unnecessary in a 351(k) application. FDA has articulated in guidance to industry that it will use a totality of the evidence approach to review applications for biosimilar products, consistent with a longstanding Agency approach to evaluation of scientific evidence.  


What is analytic similarity?

Dr. Christl: Analytic similarity studies generate data to characterize the reference product variability and product quality characteristics, characterize the proposed biosimilar product quality characteristics and variability, and identify and evaluate the potential impact of observed differences between the proposed biosimilar product and the reference product. The sponsor must demonstrate that the products are highly similar. The potential effect of differences on safety, purity, and potency should be addressed and supported by appropriate data.

Analytic similarity data are the foundation of a biosimilar development program and provide the necessary extensive structural and functional characterization of the molecule (critical quality attributes and clinically active components and the impact of manufacturing changes that occur during product development) and an understanding of the relationship between quality attributes and the clinical safety and efficacy profile. This aids in determining the residual uncertainty about biosimilarity and in predicting expected clinical similarity. 

Role of Clinical Studies

What clinical studies are expected?

Dr. Christl: As a scientific matter, FDA expects an adequate clinical pharmacokinetic and pharmacodynamic (if relevant, eg, the endpoint reflects the biologic effect(s) of the product) comparison between the proposed biosimilar product and the reference product. Also, as a scientific matter, at least one clinical study that includes a comparison of the immunogenicity of the proposed and reference product generally will be expected. A comparative clinical study will be necessary to support demonstration of biosimilarity if there are residual uncertainties about whether there are clinically meaningful differences between the proposed and reference products based on structural and functional characterization, animal testing, human pharmacokinetic and pharmacodynamic data, and clinical immunogenicity assessment.


Can you tell us more about the clinical studies that may be necessary?

Dr. Christl: If analytic differences have been observed, then any clinical study should be designed to best evaluate their potential impact.

A comparative clinical pharmacokinetic study is generally expected, and pharmacodynamic data are desirable on a case-by-case basis. The goal is to demonstrate similarity by assessing whether there are clinically meaningful differences in pharmacokinetics (and pharmacodynamics) between the proposed biosimilar and the reference product. The assumption is that similar exposure (and pharmacodynamic response) will provide similar efficacy and safety (ie, an exposure-response relationship exists). Depending on the product, the study may be conducted in healthy volunteers or patients.

A comparative clinical study for a biosimilar development program should be designed to investigate whether there are clinically meaningful differences between the proposed product and the reference product. Important determinants of the study design can include the complexity of the product; limitations of analytic testing; the extent of knowledge about critical quality attributes; the degree of understanding of the mechanism of action of the reference product; the extent of knowledge about how differences in analytic, animal, and clinical pharmacokinetics or pharmacodynamics predict differences in clinical outcome; and the sensitivity of the study design (eg, population, dose, endpoint[s]).

An adequate scientific justification must be provided for the choice of study design, study population, study endpoint(s), estimated effect size for the reference product, and study margin(s). The potential exists for a biosimilar product to be approved for one or more conditions of use for which the U.S.-licensed reference product is licensed based on extrapolation of clinical data intended to demonstrate biosimilarity in one condition of use. Sufficient scientific justification for extrapolation is necessary.  


You mentioned a “totality-of-the-evidence” approach. Can you elaborate ­further?

Dr. Christl: There is no single study that will demonstrate biosimilarity. That is why FDA recommends a stepwise approach to data generation and evaluation of residual uncertainty at each step. If analytic differences are observed, their potential impact(s) should be evaluated before proceeding to the next step in development.

For example, the results of analytic studies would provide information on the animal studies that would be warranted as the next step in evaluating residual uncertainty, and the results of the analytic and animal studies would provide information needed for the design of clinical pharmacokinetic and pharmacodynamics studies and the clinical immunogenicity assessment. All of these data together would be used to determine the residual uncertainty about the biosimilarity of the two products and the type of additional clinical data that would be needed.

First Biosimilar Marketing Application

FDA held a meeting of the Oncology Drug Advisory Committee (ODAC) on January 7, 2015, which was the first biosimilar marketing application discussed at a public advisory committee meeting. Could you summarize what kind of molecule was under review and its history?

Dr. Deisseroth: Sandoz submitted a 351(k) biologics license application requesting licensure of a granulocyte colony-stimulating factor (G-CSF) product, referred to during development as EP2006, as a biosimilar to U.S.-licensed filgrastim (Neupogen). Filgrastim is an analog of G-CSF, a hematopoietic growth factor that induces proliferation and differentiation of neutrophil-committed progenitor cells into neutrophils. Filgrastim also induces the release of neutrophils as well as CD34-positive hematopoietic progenitor cells from the marrow into the peripheral blood. Filgrastim is made up of 175 amino acids without glycosylation, so, from a molecular perspective, this product may be one of the easier ones to replicate in terms of manufacturing.

In its application, Sandoz requested that EP2006 be designated as a biosimilar to filgrastim for all of its five currently approved indications; they include decreasing the incidence of infections in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs; reducing the duration of neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation; reducing the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia; mobilizing hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid leuekmia.

Since 2009, Sandoz has marketed Zarzio, a European Union (EU)–approved biosimilar product to EU-approved filgrastim. Marketing experience with  biosimilar filgrastim outside of the United States includes in excess of 7.5 million days of patient exposure.


What did Sandoz present at the advisory committee meeting, and what was the reaction of FDA to this presentation?

Dr. Deisseroth: The foundation of biosimilar applications and a key hurdle to surmount is whether the biosimilar product is “highly similar” to the reference product from an analytic perspective. FDA agreed with the conclusions of Sandoz that EP2006 is “highly ­similar” to U.S.-licensed filgrastim based on its extensive studies of the physicochemical and functional properties of the two products. FDA also agreed with Sandoz’s conclusion that its nonclinical studies supported a demonstration of biosimilarity of its product, EP2006, to U.S.-licensed filgrastim. 

Sandoz then summarized its extensive clinical pharmacokinetic and pharmacodynamic studies in normal human subjects comparing biosimilar filgrastim with both U.S.-licensed filgrastim and EU-approved filgrastim at a wide range of doses. It is important to note that it was necessary for Sandoz to build a scientific bridge between biosimilar filgrastim, EU-approved filgrastim, and U.S.-licensed filgrastim to justify the relevance of the data generated using EU-approved filgrastim as part of the basis demonstrating biosimilarity to U.S.-licensed filgrastim.

Sandoz also summarized immunogenicity and safety evaluations, which had been carried out in normal human subjects and in patients with breast cancer. FDA agreed with Sandoz that these studies did not show any clinically meaningful differences between the products, which is the second criterion for demonstrating biosimilarity of two products.

Finally, Sandoz presented safety, efficacy, and immunogenicity data from a comparative clinical study that randomized patients with breast cancer receiving chemotherapy between biosimilar filgrastim and U.S.-licensed filgrastim to support its conclusion that there were no clinically meaningful ­differences between biosimilar filgrastim and U.S.-­licensed filgrastim. FDA commented that although it agreed with Sandoz’s conclusions, a sponsor generally will not need to conduct a comparative clinical study to evaluate efficacy and safety to support demonstration of biosimilarity unless there are residual uncertainties from the analytic, animal, and/or clinical pharmacokinetic and pharmacodynamic studies that need to be evaluated further.

The final issue addressed by the advisory committee was whether biosimilar filgrastim should be licensed for all of the five indications for which filgrastim is currently approved. FDA recommended that biosimilar filgrastim be licensed for all five of the filgrastim indications due to the common mechanism of action for all of these indications and the totality of the evidence presented by Sandoz. The advisory committee voted unanimously that biosimilar filgrastim should receive licensure as a biosimilar to U.S.-licensed filgrastim for all of the indications for which filgrastim is currently approved.

Final Comments

What are your final comments about biosimilar development?

Dr. Christl: There is no “one-size-fits-all” development plan for a biosimilar. The principles discussed herein and as outlined in FDA guidances ( should be used. FDA scientists are available to meet with companies at each step of development and when an application is submitted to evaluate the applicant’s integration of various types of information to determine whether the applicant’s product is biosimilar to the reference product. Additional information can be found at

Note: On March 6, 2015, subsequent to this interview, FDA licensed the product discussed in this article as Zarxio (filgrastim-sndz), a biosimilar to U.S.-licensed filgrastim. More information about the approval of this biosimilar can be found at ■

Disclosure: Drs. Christl and Deisseroth reported no potential conflicts of interest.


Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of
Hematology and Oncology Products.