Biosimilars Facts

What are Biologics?

Biological products—biologics—have vastly improved the treatment of conditions such as rheumatoid arthritis, anemia, leukopenia, inflammatory bowel disease, psoriasis, and various forms of cancer. The first biologic (human insulin) was marketed in 1982. Today, biologics are one of the fastest growing segments of the prescription product market.

 

Biologics are derived utilizing cells and tissue from living organisms such as humans, animals, and microorganisms such as yeast or bacteria. Vaccines, blood components, tissue, somatic cells and recombinant products can all be categorized as biologics. Biological products usually are manufactured using biotechnology methods (e.g., recombinant DNA technology) or other cutting-edge technologies. For example, human insulin was created by growing insulin proteins in a laboratory within Escherichia coli (E. coli) bacteria.

 

Biologics are different from the type of conventional medications familiar to most people. Conventional medications (also known as small-molecule drugs) are made from pure chemical substances, and their structure can be identified and characterized relatively easily. They usually are synthesized through a predictable chemical process according to a reproducible “recipe.”

 

Because biologics come from living organisms, they have larger molecules (or mixtures of molecules) and more complex structures than conventional medications. There is natural variability within biologic products. They are not easily identified or characterized, and they cannot be made by following a reproducible recipe. Consequently, the manufacturing process for biologics is far more complicated—and expensive—than it is for conventional medications. Biologics have consistent safety and effectiveness, in spite of this complexity and variability.

 

Biologics are generally more expensive than conventional medications, but they have alleviated disease burden where conventional medications were less effective. It is undeniable biologics play a vital role in improving patient outcomes for many complex diseases.

 

Source:

  • Biologics Evaluation and Research. What Are "Biologics" Questions and Answers. U.S. Food and Drug Administration. https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers. Published 2018. Accessed April 9, 2020.
What are Biosimilars?

A biosimilar is a biologic product that is developed to be highly similar to a biologic already approved by the U.S. Food and Drug Administration (FDA), known as the reference product. A biosimilar is a biologic. Biologics, including biosimilars, are derived from living cells. There is a degree of natural variability in all biologic products; it is not possible to generate a precise copy of a product that comes from living cells. All biologics—including reference products—show some batch-to-batch variation.

 

Even so, biosimilars are shown to be highly similar to the reference product, with no clinically meaningful difference in safety or effectiveness. Only minor differences among clinically inactive components is allowed. Any such differences are carefully evaluated by the FDA to ensure that safety and quality standards have been met before gaining approval. Moreover, the manufacturer is responsible for demonstrating that the biosimilar has no meaningful differences in terms of safety, purity and effectiveness when compared to its counterpart. 

 

The following list contains all the biosimilars that have been approved in the United States thus far. Additionally the Purple Book can also be accessed for additional information.

https://www.fda.gov/drugs/biosimilars/biosimilar-product-information

 

Source:

  • Biologics Evaluation and Research. What Are "Biologics" Questions and Answers. U.S. Food and Drug Administration. https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers. Published 2018. Accessed April 9, 2020.
How are Biosimilars Regulated?

The European Medicines Agency (EMA) was the first regulatory agency to develop an overarching framework for the approval of biosimilars. Biosimilars have been approved for use in the European Union since 2006; and subsequently have been approved for use in Australia, Japan, and Latin America. The World Health Organization (WHO) has also developed guidelines for similar biotherapeutic products (also known as biosimilars) to ensure that biosimilars produced and utilized in different countries comply with international standards. 

In the United States, a regulatory pathway for approval of biosimilars was made possible by the Biologics Price Competition and Innovation Act of 2009 (BPCIA), a provision included in the Patient Protection and Affordable Care Act of 2010. The BPCIA created an abbreviated licensure (approval) pathway for biosimilar products to promote industry innovation, reduction in healthcare costs, and increase access to these biological medications. The U.S. Food and Drug Administration (FDA) evaluates the proposed biosimilar product against the reference product to establish that there are not any clinically meaningful differences between the two products in terms of efficacy, safety, and quality. The biosimilar products must prove that they have the same mechanism of action, route of administration, dosage form, and strength as the reference product. The biosimilar product may be approved only for the indications and conditions of use that have been approved for the reference product.

Source:

  • Biosimilars in the EU. https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf. Accessed April 8, 2020.
  • Center for Drug Evaluation and Research. Scientific Considerations in Demonstrating Biosimilarity. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product. Accessed April 4, 2020.
  • Kang H-N, Knezevic I. Regulatory evaluation of biosimilars throughout their product life-cycle. Bulletin of the World Health Organization. 2018;96(4):281-285. doi:10.2471/blt.17.206284.
  • O’Callaghan J, Barry SP, Bermingham M, Morris JM, Griffin BT. Regulation of biosimilar medicines and current perspectives on interchangeability and policy. European Journal of Clinical Pharmacology. 2018;75(1):1-11. doi:10.1007/s00228-018-2542-1.
How Does a Manufacturer Demonstrate Biosimilarity?

There is no single study that will demonstrate biosimilarity. The FDA uses a “totality of the evidence” approach to review applications for biosimilar products. Manufacturers must provide data from:

  • Analytic studies demonstrating that the structure and function of the biosimilar are “highly similar” to the reference product.
  • Animal studies, including assessment of toxicity.
  • A clinical study or studies, including assessment of immunogenicity (whether the biosimilar produces an unwanted immune response) and pharmacokinetics or pharmacodynamics.

The FDA pathway for approving reference biologics emphasizes large clinical studies that establish safety and efficacy. In contrast, the pathway for approving biosimilars places greater emphasis on biological and physicochemical characterizations of the biosimilar molecule, because the safety and efficacy data for the reference product are readily available.

Studies to establish biosimilarity are intended to be conducted in a stepwise manner. Ideally, extensive initial analytic testing demonstrates minimal or no qualitative or quantitative differences in the structure and function of the proposed biosimilar and the reference product. The similarity of the proposed biosimilar and the reference product is confirmed using subsequent animal studies. Any unanswered questions, called “residual uncertainty”, about the clinical safety and efficacy of the proposed biosimilar are addressed in clinical assessments of immunogenicity and pharmacokinetic or pharmacodynamic studies. If residual uncertainty remained after those studies, additional clinical studies would be conducted to confirm the safety and efficacy of the proposed biosimilar.

Ultimately, FDA reviews a totality of evidence to establish that a biosimilar is essentially the same drug as the reference product, and that it will work the same way as the reference product for its approved indications. At the point a biosimilar is approved by the FDA, any differences that exist between the biosimilar and the reference product will have been shown not to affect efficacy or safety.

The illustration provides an overview of how FDA reviews evidence to approve biologics and biosimilars.

Source:

  • Center for Drug Evaluation and Research. Scientific Considerations in Demonstrating Biosimilarity. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product. Accessed April 8, 2020.
  • O’Callaghan J, Barry SP, Bermingham M, Morris JM, Griffin BT. Regulation of biosimilar medicines and current perspectives on interchangeability and policy. European Journal of Clinical Pharmacology. 2018;75(1):1-11. doi:10.1007/s00228-018-2542-1.
What are Interchangeable Biologic Products?

According to the Biologics Price Competition and Innovation Act of 2009 (BPCIA), for a biosimilar product to be designated as interchangeable, the manufacturer must provide additional evidence that the biosimilar is expected to produce the same clinical result as the reference product in any given patient. In addition, the manufacturer must show that patients may use both products safely and without any loss in efficacy. Specifically, if the biosimilar is administered more than once to a patient, the risk (in terms of safety or reduced effectiveness) associated with alternating or switching between the biosimilar and the reference product cannot be greater than the risk of using the reference product continuously.

The designation of interchangeability is unique to the United States, and refers specifically to the ability of a pharmacist to substitute the interchangeable product for the reference product without the intervention of the prescriber. This process is similar to how pharmacists are able to substitute a brand name drug with its generic drug.

An interchangeable designation is not a “higher” level of approval than biosimilar approval, but instead just an additional – and expensive – set of clinical studies that the manufacturer must conduct. To date, the biosimilars available in the United States are administered by a physician or in a clinic or office setting, so interchangeability has no practical use for those products. There may be incentive for a manufacturer to pursue interchangeability for future biosimilars that are dispensed directly to patients in an ambulatory pharmacy.

To date, no biosimilar products in the United States have been designated interchangeable.

Source:

  • Center for Drug Evaluation and Research. About Biosimilars and Interchangeable Products. U.S. Food and Drug Administration. https://www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products#top. Accessed April 8, 2020.
How are Biosimilars Named and Identified?

When conventional small molecule agents are approved, the United States Adopted Names (USAN) Council assigns a nonproprietary (generic) name identifying the active medication. Similar to conventional small-molecule medications, newly approved biologics are given both a brand name (e.g., Neupogen®) and a nonproprietary (proper) name (e.g., filgrastim). The nonproprietary name reflects certain scientific characteristics of the product, such as chemical structure and pharmacological properties. Because medications may be approved for use in many countries around the world, the generic name assigned by the USAN Council usually is adopted by the World Health Organization (WHO) as the International Nonproprietary Name (INN). The INN facilitates the clear identification of medications, safe prescribing and dispensing of medications, and communication and exchange of information among health care professionals and scientists worldwide.

 

Specific rules for assigning nonproprietary names for biosimilar products in the United States had not been fully established when the first products were approved. The first biosimilar product (Zarxio®) was given a placeholder nonproprietary name of filgrastim-sndz. The U.S. Food and Drug Administration (FDA) assigned a random 4-letter suffix to the second biosimilar approved, infliximab-dyyb. In a final guidance for industry issued in March 2019, the FDA established that all newly approved biologics, including biosimilars, will have a two-part nonproprietary name, consisting of:

  1. A core name that will be the same for all products.
  2. A distinguishing suffix that is devoid of meaning and composed of four lowercase letters, separated from the core name by a hyphen.

For example, the nonproprietary name of a reference product could be replicamab-cznm, and a biosimilar to that product could be replicamab-hixf. At least three of the four lowercase letters in the suffix must be distinct.

 

The guidance does not include a naming convention for interchangeable products.

 

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