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Industry Guidance on Biosimilars

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Biological drugs can include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues and therapeutic proteins. A biosimilar is the biological equivalent of a generic drug product in the world of small molecules. The special nature of biological drugs has required regulatory agencies to develop specific requirements for their development and approval.

Biological drugs in general may be manufactured through biotechnology, derived from natural sources or, in a few cases, produced synthetically. Biological products are usually much larger than and have considerably more complex structures than small-molecule prescription drugs. This added complexity makes it much more difficult for manufacturers to prove that a biosimilar is equivalent to its reference molecule.

The term “biosimilar” has been used by regulatory agencies and industry to reflect the understanding that such a drug would not be an exact duplicate of the innovator drug. The FDA defines biosimilarity to mean that “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” 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.”

An abbreviated licensure pathway was created for biologics to demonstrate products to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. The Biologics Price Competition and Innovation Act (BPCI Act) was passed as part of the Affordable Care Act that President Obama signed into law on March 23, 2010. Under this new law, a biologic may be demonstrated to be “biosimilar” if data show that, among other things, the drug is “highly similar” to an already-approved biological product. An “interchangeable” drug is biosimilar to the reference product and can be expected to produce the same clinical result as the reference drug in any given patient.

A draft guidance for industry entitled ‘‘Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation (BPCI) Act of 2009’’ was published for comment in the Federal Register in February of this year. Answers to common questions from sponsors interested in developing proposed biosimilar products, biologics license applications holders and other interested parties regarding FDA’s interpretation of the BPCI Act were posed. One such question related specifically to use of a container closure or delivery system different from that used in its reference product.

Some design differences in the delivery device or container closure system used with the proposed biosimilar product may be acceptable. It may be possible, for example, for an applicant to obtain licensure of a proposed biosimilar product in a prefilled syringe or in an auto-injector device, even if the reference product is licensed in a vial presentation, provided that the proposed product meets the statutory standard for biosimilarity and adequate performance data for the delivery device or container closure system is provided. The presentation must be shown to be compatible for use with the final formulation of the biological product through studies such as:

  • Extractable/leachable and stability studies
  • Potential for performance testing and a human factors study for certain design differences in the delivery device or container closure system

Additional considerations apply for a proposed interchangeable product. For example, in reviewing an application for a proposed interchangeable product, FDA may consider whether the differences from the reference product significantly alter critical design attributes, product performance or operating principles, or would require additional instruction to healthcare providers or patients, for patients to be safely alternated or switched between the reference product and one or more interchangeable products without the intervention of the prescribing healthcare provider. Additional performance data about the delivery device may also be necessary. A proposed biosimilar product in a delivery device will be considered a combination product and may, in some instances, require a separate application for the device.

This draft guidance, when finalized, will represent the FDA’s current thinking on this topic. The guidance addresses a broad range of issues and will include quality considerations in demonstrating biosimilarity to a reference protein product. More information can be found at