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Key Tenets of the U.S. Biosimilars Regulatory Pathway

In the U.S., the regulatory pathway for all medicines, including biosimilars, is rigorous. At the core of the biosimilars regulatory pathway is the mandate that biosimilar sponsors must demonstrate that the biosimilar is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency.

The FDA regulatory pathway accounts for safety and efficacy for biosimilars in an analogous manner to the European Union, where biosimilars have been approved for use since 2006. As of the end of 2015, Europe had approved 12 different biosimilar products, which are now marketed under 18 different brand names. As a result, in Europe, clinicians and patients have benefited from the safe use of millions of doses of biosimilar medicines. Throughout this time, there have been no additional unexpected safety concerns about biosimilars that were not already known from the reference product.

The U.S. Regulatory Pathway for Biosimilars

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Patient Protection and Affordable Care Act (ACA) in 2010. The ACA was enacted to increase the quality and affordability of health care while reducing costs for individuals and the government. As part of this, an abbreviated licensure pathway was created for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product.

Definition of Biosimilar

According to the FDA, a biosimilar is a biological product that has been proven to be highly similar to a reference product notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency.

Definition of Interchangeable

When a biosimilar is determined to be interchangeable with its reference product, it can be expected to produce the same clinical result as the reference product in any given patient. It also must be demonstrated that for a product used more than once, the risk in terms of safety or diminished efficacy of alternating or switching between use of the interchangeable product and its reference product is not greater than the risk of using the reference product without alternating or switching.

The designation "interchangeable" or "interchangeability," in reference to a biological product that is shown to meet the standards described in the Public Health Service Act, means that the biological product may be substituted by a pharmacist for the reference product without the intervention of the health care provider who prescribed the reference product, subject to state substitution laws.

351(k) Application Pathway Requirements

By definition, manufacturers of biosimilars in the U.S. seek FDA regulatory approval through a Public Health Service Act Section 351(k) application. The application must include information demonstrating that:

  • The biological product is biosimilar to a reference product
  • It utilizes the same mechanism(s) of action for the proposed condition(s) of use (to the extent the mechanism[s] are known for the reference product)
  • Condition(s) of use proposed in labeling have been previously approved for the reference product
  • Route of administration, dosage form, and strength is the same as the reference product
  • The facility in which the biosimilar is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent

The data demonstrating biosimilarity must be derived from:

  • Analytical studies demonstrating that the biological product is “highly similar” to the reference product, notwithstanding minor differences in clinically inactive components
  • Animal studies, including the assessment of toxicity
  • A clinical study or studies, including the assessment of immunogenicity and pharmacokinetic/pharmcodynamic studies that are 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

Data demonstrating interchangeability must demonstrate that:

  • The product is biosimilar to the reference product
  • Can be expected to produce the same clinical result as the reference product in any given patient
  • For a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and its reference product is not greater than the risk of using the reference product without alternating or switching.

In the application process, the FDA may determine, at its discretion, that an element in the application process described above is unnecessary in the 351(k) application.

Biosimilars Approvals

Following submission of the complete 351(k) application, the FDA confirms that the product is indeed biosimilar to or interchangeable with the reference product. The facility where the biosimilar is manufactured must comply with the appropriate FDA inspections. At this time, the product is then officially licensed by the FDA for its designated therapy.

Sometimes manufacturers will submit a 351(k) application where some data were generated using a comparator product purchased outside of the U.S. While this is permissible in some defined circumstances, the FDA carefully reviews the data provided by the sponsor to demonstrate that the material purchased outside of the U.S. is fully comparable to equivalent U.S.-approved material. The reference product will always be the single biological product licensed previously as a new biologic (using Section 351(a) of the Public Health Service Act) against which a biosimilar is evaluated in an application submitted under Section 351(k).