The Brave New World of Biosimilars

Lauri R. Graham; Laurie Scudder, DNP, NP; Leah Christl, PhD


May 25, 2016

Editorial Collaboration

Medscape &

Editor's Note:
Biosimilars—biologic agents developed to be "highly similar" to approved drugs with expired patent protection—are now available in the United States, with the US Food and Drug Administration (FDA) approval of Zarxio® (filgrastim-sndz; Sandoz/Novartis) in March 2015 and Inflectra™ (infliximab-dyyb; Janssen Biotech) in April 2016. These agents are anticipated to bring more treatment options for patients, along with significant cost savings. But are clinicians ready for them? Medscape asked Leah Christl, PhD, associate director for therapeutic biologics in the Center for Drug Evaluation and Research at the FDA, to address the key issues they want healthcare professionals to understand.

Biosimilars vs Brand-Name Drugs

Leah Christl, PhD, Associate Director, Therapeutic Biologics, Center for Drug Evaluation and Research, US Food and Drug Administration

Medscape: What is a biosimilar product, and how does it compare with and differ from a brand-name biologic product?

Dr Christl: A biosimilar product is defined as a biological product that is highly similar to the reference product, notwithstanding minor differences in clinically inactive components. There are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.

FDA interprets the terms "safety, purity, and potency" to mean "safety and effectiveness." FDA uses the term "reference product" to mean the FDA-approved biological product with which the biosimilar product is compared in its marketing application.

Medscape: What types of biological products are regulated by the FDA?

Dr Christl: The FDA regulates three types of biological products:

  1. Originator biological products (also called "reference products"). Approval of an originator biological product is based on a full complement of data, including nonclinical and clinical data that demonstrate that the product is safe and effective.

  2. Biosimilar products. Approval of a biosimilar product is based on showing that it is highly similar to and has no clinically meaningful differences from the reference product in terms of safety, purity, and potency (safety and effectiveness).

  3. Interchangeable products. An interchangeable product must not only be shown to be biosimilar to the reference product, but the sponsor also must demonstrate that the proposed interchangeable product is expected to produce the same clinical result as the reference product in any given patient. In addition, when a product will be administered more than once to an individual, the sponsor must also demonstrate that the risk (in terms of safety or reduced effectiveness) of alternating or switching between using proposed interchangeable biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.


Medscape: What is the difference between a biosimilar drug and a generic drug?

Dr Christl: A generic drug is chemically identical to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. As a result, different manufacturers can produce what are essentially exact copies of the brand-name product.

Biological products are larger, more complex molecules that are more difficult to characterize. These products are generally produced in a living system, such as a microorganism or plant or animal cell. The nature of biological products, as well as the natural variations in their manufacturing, creates unique challenges that generally do not exist in small-molecule drugs.

This increased complexity helps to underscore why biosimilars are regulated differently from generic drugs, and why the law allows some differences between the biosimilar and the reference product. However, a biosimilar product must be the same dosage form, route of administration, and strength as the reference product.

All FDA-approved drugs and biological products have met the FDA's standard for approval and have been determined to be safe and effective under the conditions of use described in approved product labeling. Although the overarching goals and requirements for biological products generally are the same as for small-molecule drug products, there are additional requirements for biological products, because biological products are generally more complex than small-molecule drugs. They are also regulated under different laws and statutes.

Medscape: What testing must be done to demonstrate biosimilarity?

Dr Christl: FDA uses a totality-of-the-evidence approach when reviewing a marketing application for a proposed biosimilar product. The approach considers all available data and information submitted by the sponsor, including (as appropriate) analytical, animal, human pharmacokinetic and pharmacodynamic, clinical immunogenicity, and clinical safety and effectiveness data.

The marketing application should include the data needed to show that there are no clinically meaningful differences (including in immune response) between a proposed biosimilar product and the reference product. This is a key element in the demonstration of biosimilarity. The goal of the clinical immunogenicity assessment is to evaluate potential differences between the proposed biosimilar product and the reference product in the incidence and severity of human immune responses. Immune responses may affect both the safety and effectiveness of the product by, for example, altering pharmacokinetics, inducing anaphylaxis, or promoting development of antibodies that neutralize the product as well as its endogenous protein counterpart. Therefore, the sponsor is expected to conduct at least one clinical study that includes a comparison of the immunogenicity of the proposed biosimilar product with that of the reference product.

In addition, to demonstrate that the proposed product is highly similar to the reference product, a sponsor should conduct an extensive comparative analytical program. For example, sponsors generally will need to conduct comparative analyses of primary structures, higher-order structures, posttranslational modifications, other variants (eg, protein deamidation and oxidation), and biological functions, in addition to conducting an analysis of impurities.

FDA recommends that sponsors submit analytical data to the FDA before conducting clinical studies. The nature and scope of clinical studies will depend on the extent of residual uncertainty about the proposed biosimilar product after conducting structural and functional characterization and, where relevant, animal studies. As a scientific matter, FDA generally expects that sponsors will conduct a pharmacokinetic and (if appropriate and relevant) pharmacodynamic comparison of the proposed biosimilar product and the reference product. Sponsors may also need to conduct a comparative clinical study to further assess whether there are clinically meaningful differences between the products.

Medscape: Does a sponsor have to establish the safety and efficacy of the biosimilar?

Dr Christl: FDA does not require that a sponsor independently establish the safety and efficacy of the proposed biosimilar for each proposed condition of use (eg, indication). As such, the comparative clinical study may use endpoints (eg, response rate or some other pharmacodynamic endpoint) or populations to investigate whether there are clinically meaningful differences between the products that are different from the endpoints that were used to independently establish the safety and efficacy of the reference product. Furthermore, FDA will assess whether meaningful differences exist in relevant safety parameters.

Clinical Indications for Biosimilars

Medscape: Will biosimilars be approved for the same indications as the reference product? How will indications be determined?

Dr Christl: Generally, a biosimilar cannot be approved for a specific condition of use or indication that is not already approved for the reference product. A biosimilar sponsor may seek approval for all conditions of use and indications or for fewer than all conditions of use and indications for which the reference product is approved. That means that the biosimilar sponsor may decide not to seek approval for all of the indications for which the reference product is approved. Or exclusivity and patent protections might exist for certain indications that preclude the biosimilar product from receiving approval for those indications.

A new indication will not be automatically added to the biosimilar product if the reference product seeks and gains approval for a new indication. Biosimilar application holders who want to seek approval for additional condition(s) of use or indication(s) after initial product approval must submit supplement(s) to their 351(k) biologics license application that contains the necessary data and information, including draft labeling revised to include the additional condition(s) of use or indication(s) sought.

Medscape: Because it's not feasible to perform clinical studies for all proposed indications within the confines of the proposed guidelines for biosimilar development, how can clinicians be certain that a biosimilar will be effective if it's used for nonapproved indications or indications that differ from approvals for the reference product?

Dr Christl: A determination of biosimilarity by the FDA means that the biosimilar product is expected to have the same safety and efficacy and risk/benefit profile as the reference product for the approved indications. To determine which indications have been approved for a biosimilar product, healthcare professionals are advised to review the labeling—prescribing information—of the biosimilar product. FDA does not regulate the practice of medicine. It is a clinician's decision on whether to prescribe a biosimilar product for a use not listed in its FDA-approved labeling.

Medscape: What advice can you provide to clinicians, particularly in counseling patients about biosimilars? For example, consider a patient who is leery about switching to a biosimilar, when he or she is happy with the brand-name drug.

Dr Christl: Healthcare professionals are advised to review the labeling (prescribing information) of the biosimilar product to determine the conditions of use for which the biosimilar is approved. Patients and healthcare professionals will be able to rely on the safety and effectiveness of the biosimilar or interchangeable product for its approved indications, just as they would for the reference product. If a patient is prescribed a biosimilar product, he or she can expect it to work in the body in the same way as the reference product. The availability of biosimilar and interchangeable biological products can provide more treatment options for patients, and possibly lower treatment costs, enabling greater access for more patients.

Regulation and Naming

Medscape: Does FDA approve biosimilars in the same way as generic drugs?

Dr Christl: Generics and biosimilars are regulated under different legal statutes. For biosimilars, the legal statute is the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which is part of the Affordable Care Act. The BPCI Act created a new approval pathway for products that are biosimilar to or interchangeable with an FDA-licensed reference product (an already licensed FDA biological product).

The sponsor of a proposed biological product that is demonstrated to be biosimilar to a reference product can rely on FDA's previous finding of safety and effectiveness for the reference product. The ability to rely on certain existing scientific knowledge about the reference product to support the safety and effectiveness of the biosimilar product allows for a potentially shorter and less costly drug development program. This is what is meant by an abbreviated approval pathway, and it is one way to improve access and increase treatment options for the public at potentially lower cost.

A biosimilar product's reliance on the safety and efficacy of the reference product is similar in concept to a generic drug's reliance on the safety and efficacy of the brand-name product. However, the comparative analytical and clinical data that support the demonstration of biosimilarity are different from the data required to demonstrate bioequivalence of a generic drug.

Medscape: How are biosimilars named?

Dr Christl: The FDA published draft guidance on the nonproprietary naming of biological products that describes FDA's current thinking on the appropriate naming convention, to help ensure the safety of patients receiving biological products and maximize the success of biosimilar and interchangeable biological products. We believe that both reference products and biosimilars should have nonproprietary names (also called a "proper name") that include a core drug substance name and, to facilitate safe use and pharmacovigilance, an FDA-designated suffix that is unique to each product. The FDA is committed to carefully reviewing the comments received as we move forward in finalizing the draft guidance.

Postmarketing Monitoring of Biosimilars

Medscape: After a biosimilar comes to market, what monitoring is needed?

Dr Christl: Robust postmarketing safety monitoring is an important component in ensuring the safety and effectiveness of biological products, including biosimilar products. Many factors influence postmarketing safety monitoring considerations, including but not limited to any particular safety or effectiveness concerns associated with the use of the reference product and other products in the class, data on the proposed product obtained during its development and clinical use (if marketed outside the United States), and the specific condition(s) of use and patient population(s) in whom the product will be used. Such considerations will be made on a product-specific basis.

Medscape: For the two biosimilar products that have been approved, have postmarketing data to date raised any safety or effectiveness concerns?

Dr Christl: Zarxio began marketing in the United States in September 2015, and FDA did not receive any adverse event reports for the most recent reporting period of October-December 2015. Inflectra has not yet begun (ie, as of the time of this interview) marketing in the United States.

Substitution of Brand-Name Drugs With Biosimilars

Medscape: How will substitution for the brand-name drug be allowed and regulated?

Dr Christl: Healthcare providers can prescribe biosimilar and interchangeable biological products just as they would prescribeother medications. Pharmacy practices related to substitution are generally governed by state law, and the specific laws for substitution of interchangeable products may vary from state to state.

The BPCI Act describes an interchangeable product as a product that may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. In contrast, FDA expects that a biosimilar product will be specifically prescribed by the healthcare provider and cannot be substituted for a reference product at the pharmacy level.

Medscape: What is the best process for considering therapeutic interchange?

Dr Christl: The FDA has published the Purple Book: Lists of Licensed Biological Products With Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations online. The Purple Book provides a convenient source of information on whether a biological product has been determined by the FDA to be biosimilar to or interchangeable with a reference product (an already licensed FDA biological product). Biosimilar and interchangeable biological products will be listed under the reference product to which biosimilarity or interchangeability was demonstrated.

Medscape: Are pharmacists required to notify prescribers about substitution with biosimilars or maintain any specific recordkeeping?

Dr Christl: Pharmacy practices related to substitution are generally governed by state law, and the requirements will vary among states.

Where to Learn More

Medscape: Where can clinicians find information about biosimilars and biosimilarity?

Dr Christl: FDA recently released a continuing education course, FDA Overview of Biosimilar Products, that shares important information about biosimilar and interchangeable products to help healthcare professionals make informed decisions when considering, prescribing, or dispensing biosimilar products. This course also provides a general overview of FDA's scientific approach to the development of biosimilar products. Additional training and continuing education courses can be found online.

FDA also posts many guidance documents on their website that spell out FDA's thinking about several scientific and policy issues for biosimilars.

More product-specific information about approved biosimilars can be found at Drugs@FDA.