Biosimilar Approval Process: Preparing for FDA Review and a Possible Advisory Committee Meeting

The FDA approved Zarxio filgrastim, the first biosimilar product in the United States in March 2015, under the Biologics Price Competition and Innovation Act of 2010.

While there is now a marketed biosimilar, a formal biosimilar approval pathway, and FDA guidance documents for biosimilars; the FDA is still grappling with this new area.

The need to integrate non-clinical and clinical data leaves sponsors with a lack of clarity on many aspects of the biosimilar approval process. These issues include: interpreting FDA advice on submission needs; responding to FDA questions during review; and developing messages for a potential FDA advisory committee meeting.

This uncertainty is compounded by expert consultants and advisory committee members, who may not have the specific expertise to address this still-evolving area of biosimilar data analysis.

This article highlights some of the unique and important aspects sponsors will have to consider in preparing their biosimilar applications to the FDA and an FDA advisory committee meeting. It also includes recommendations from 3D Communications on how to address these considerations.

  1. A biosimilar review is different from a New Molecular Entity (NCE) review.The nature of a biosimilar approval differs distinctly from a novel chemical entity (NCE). A biosimilar, a biological product that is highly similar to a US-licensed reference biological product, uses an abbreviated licensure pathway that is not intended to independently determine the benefit-risk of the product. The FDA guidance states:

    “To demonstrate biosimilarity, a sponsor must provide sufficient data and information to show that the proposed product and the reference product are highly similar notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the two products in terms of safety, purity, and potency.”[1]

    The FDA will use a Totality of the Evidence approach to determine biosimilarity, based on a step-wise evaluation process. Sponsors have been advised to use a “pyramid” development pathway, “…which can include a comparison of the proposed product and the reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness.”[1]


    This model reflects FDA’s thinking and is meant to first establish similarity between the biosimilar molecule and the reference product. Each step up the pyramid either reinforces the established physicochemical similarity between the two products or addresses any residual uncertainties.

    Implications/Recommendations: Since the resulting differences between biosimilar and NCE reviews affect the content of the application, interactions with the FDA, the need for expert opinion, and preparations for a possible advisory committee meeting, sponsors should not be compelled to conform to a “traditional” Common Technical Document (CTD) application for approval format. Rather, due to the enhanced need for non-clinical and pharmacology evidence, and diminished need for clinical data, they will need to more closely integrate non-clinical and clinical data.

  2. In a biosimilar review, there is an increased emphasis on analytics (physicocochemical/biological function) and clinical pharmacology.A biosimilar product must have analytical confirmation of a “highly similar” physicochemical structure and biological function, along with pharmacokinetic (PK) bioequivalence and pharmacodynamic (PD) similarity that enable the biosimilar to rely on the wealth of data established during development and marketing of the reference product. This changes the emphasis of regulatory review from clinical efficacy and safety to include broader examination of at least three areas:

    • Analytics (e.g., CMC, physicochemical structure, biological function);
    • Clinical Pharmacology (i.e., PK/PD); and
    • Clinical Efficacy and Safety.

    As shown in the pyramid development paradigm above, the analytical result will inform the need for clinical data. As such, there is an increased emphasis on non-clinical to clinical “cause-and-effect” investigations that require an explicit link between the non-clinical hypothesis and the clinical outcomes. Because of this, there is a need for a much broader expertise, as well the ability to understand and anticipate how all three areas (analytics, clinical pharmacology and clinical efficacy and safety) interconnect and influence each other. Importantly, FDA reviewers and advisory committee members must be able to determine whether the identified differences are clinically meaningful.

    When sponsors prepare their development plan, create the application documents, and prepare for a possible advisory committee, they should seek advice from appropriate experts with diverse backgrounds including analytics (experts including but not limited to CMC, biochemistry and pharmaceutical sciences), and pharmacology, so they can integrate the “totality of evidence” as well as address the needs of each member.

  3. In-depth review of structural and functional similarity is essential.The first, and arguably most important step, in showing biosimilarity to the reference product is the analytical assessment of physicochemical structure and biological function. Some differences among large, complex molecules are inevitable and expected, and these need to be identified.

    Implications/Recommendations: Sponsors must identify and investigate these differences to demonstrate that each difference is not clinical meaningful. They should then systematically evaluate differences that could lead to a potential change in efficacy or safety. This will enable them to demonstrate to the FDA and/or relevant consultants that adequate and accurate investigations were conducted and that there are no clinically meaningful differences from the reference product.

  4. Sponsors must link analytics with expected clinical outcomes.Because FDA requires that a biosimilar both demonstrate a “highly similar” physiocochemical structure and biological function to the reference product – as well as any potential impact from structural differences on clinical outcomes — sponsors must link pharmaceutical science data with clinical data. This, then, requires a much more systematic and detailed review than for an NCE.Sponsors should comprehensively demonstrate analytical similarities, removing the need for additional assessments. Each identified structural difference will need to be assessed for relative risk, and ranked by importance to clinical function (i.e., defined by guidance documents as “residual uncertainty”). These will then need to be thoroughly evaluated to demonstrate that each theoretical clinical difference is, in fact, not clinically meaningful. In all cases, the sponsor needs appropriate – albeit abbreviated – clinical data to show that there are no clinically meaningful differences between the biosimilar and the reference product.Implications/Recommendations: In each case, the assessment and communications need to clearly link the analytical differences between the biosimilar and reference product with the clinical outcome. This will lead to more detailed explanations in the application sections of the submission document, briefing documents, and potential presentations to an advisory committee.
  5. There is a need to address a knowledge gap between analytical and clinical reviewers and advisors.While there is a need to connect analytical assessments with clinical expectations, the experts in these respective fields lack knowledge of the other. Analytical reviewers, have a different knowledge base than clinical experts, and understandably neither has the background to fully comprehend each other’s perspective. This is not unexpected due to the complexity of the science and different training pathway.

    Yet, all these experts need to understand how the totality of the data “fit together” to fulfill the biosimilar requirement.Implications/Recommendations: Messages to the FDA and a potential advisory committee need to be communicated in a way that is credible, yet remain simple enough to be understood by those with incomplete knowledge. This will likely expand the length of written communications. It will also require that the submission and briefing documents are organized in an intuitive way. The goal is to allow each type of expert (i.e., analytics, clinical pharmacology and clinical efficacy and safety) to find specific data, while not overwhelming them with data they do not know how to interpret.


In general, biosimilar applications have unique needs that distinguish them from NCE applications and sponsors must explicitly consider the differences when preparing for an FDA submission or an advisory committee meeting. Even though there is precedent of a biosimilar approval with Zarxio filgrastim, given the implications of submissions of more complex molecules like monoclonal antibodies, there may be few transferrable leanings.

As this is an evolving area of regulatory approval, sponsors can expect to face many practical challenges. These range from interpreting FDA advice on submission needs, to preparing materials for FDA reviewers and advisory committee members who may not have the specific expertise to address biosimilar data analysis. As a result, sponsors need to adopt a rigorous process to prepare for these communications. Awareness of this situation and early preparations – including expert consultations – can help companies best prepare for these uncertainties and risks.


[1]   Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (February 2012)



headshot-kell-cannonKell Cannon brings more than 20 years of U.S. and global lifecycle and pharmaceutical marketing expertise to 3D’s clients. Kell has developed rigorous processes to help clients analyze and prepare their regulatory submissions and FDA Advisory Committee presentations. This assistance enables companies to win approval, expedite product access, and achieve competitive reimbursement. Connect with Kell on LinkedIn.

Cox_Virginia_2015_HeadshotVirginia Cox, JD, is a Senior Consultant and 3D Communications lead.  Before joining 3D, Virginia was the Associate Commissioner for the Office of External Affairs at the U.S. Food and Drug Administration (FDA). Her FDA experience, along with her role as a Communications Lead on numerous 3D FDA Advisory. Committee projects, uniquely qualifies her to provide important perspectives on this topic. Connect with Virginia on LinkedIn.