Rigorous Development and Regulatory Pathways

Developing a biosimilar is an incredibly complex process. Biosimilars, like all biologics, are produced through an intricate, multistep process, using living cells.^1,2 The technology we're using to develop and manufacture biologics today is more precise, more accurate, and more quantitative than in years past—giving us the ability to look at multiple attributes to bring reliable, high-quality medicines to patients.^1-5 

What are biologics?

A biologic is a substance derived from a living organism or its products, used to diagnose, prevent, or treat disease.⁶ Examples of biologic medicines include recombinant proteins, allergy shots and vaccines.⁶

What are generics?

A generic is a chemically synthesized drug that has the same active ingredient, strength, dosage form, route of administration, and conditions of use as its reference drug.⁷

What are biosimilars?

A biosimilar is a biological product that is highly similar to an approved reference product with no clinically meaningful differences in terms of the safety, purity, and potency of the product.⁸

Biosimilars are not generics.

End-to-End Biologics Experts: Our Process

At Amgen, we excel at the highly specialized, iterative process of developing monoclonal antibodies in vitro, scaling up the optimal cell line, time and again, in large-scale bioreactors, and checking and rechecking for batch-to-batch consistency.^1,9

The regulatory approval pathway for biosimilars, while distinct from the pathway for reference products, is rigorous and scientifically appropriate.⁹

Regulatory Approval Pathways

The approval pathway for biosimilars is rigorous and scientifically appropriate.^1,9 Sustaining biosimilar success and confidence in this critical class of medicines is dependent on maintaining these regulatory and scientific standards.

Proven Biosimilarity

Biosimilars must demonstrate high similarity to the reference product.^1,9 This includes a comprehensive comparison of the quality attributes of the biosimilar molecule with the reference product to ensure the products are highly similar on a structural and functional level.^1,9 Similarity of the biosimilar's strength and dosing, and route of administration must also be demonstrated.

Biosimilars cannot be approved for use on analytical data alone. Additional data, including nonclinical, where relevant, and clinical data, must be provided.^1,9

Clinical Testing

Regulatory bodies, like the U.S. Food and Drug Administration (FDA), require manufacturers to generate robust and rigorous data for each biosimilar medicine before it undergoes regulatory review to ensure the biosimilar is highly similar to its reference product with no clinically meaningful differences in efficacy, safety, or immunogenicity.^1,9 This includes: 

• Same treatment benefits and risks
• No meaningful differences in effectiveness or possible side effects^1,9 

Clinical requirements for biosimilar development may differ by regulatory agency. 

Comparative Clinical Studies

Comparative clinical studies are generally needed to demonstrate that there are no clinically meaningful differences between a biosimilar and its reference product.^1,9 This demonstration can be supported through comparative pharmacokinetic, pharmacodynamic, safety, immunogenicity, and efficacy data. The type and amount of clinical data is dependent on the specific development program.

U.S. law already permits the FDA to not require comparative clinical efficacy data in a biosimilar application when appropriate.^1,9

Extrapolation

Extrapolation of data is used to support the approval of a proposed biosimilar product in one or more additional indications for which the reference product is licensed, based on the totality of the evidence and appropriate scientific justification.¹⁰

Totality of Evidence Demonstrates Similarity

The U.S. Food and Drug Administration (FDA) approves biosimilars using a "totality-of-the-evidence approach", allowing for a more streamlined development pathway compared to that of a reference biologic. This means manufacturers are not required to generate the full package of clinical and nonclinical data necessary for the approval of the original reference product. The FDA instead uses multiple types of evidence to determine biosimilarity that may include:

• Extensive analytical testing to assess structural and functional similarity between the biosimilar and the reference product
• Clinical Pharmacology studies to evaluate how the drug behaves in patients' bodies
• A clinical study confirming there are no clinically meaningful differences in safety, purity, and potency in at least one of the approved uses of the reference product.

The FDA may determine on a case-by-case basis that certain elements of this evidence package are not needed to demonstrate biosimilarity.

What is the Interchangeability Standard for Biosimilars?

In the U.S., an "interchangeability" designation means the biosimilar may be substituted for its reference product at the pharmacy in accordance with state laws.   

In the EU, interchangeability relates to prescribing where a physician may elect to prescribe one medicine to a patient in place of another with the same therapeutic intent.^2,4 The European Medicines Agency (EMA) has not taken a position on pharmacy substitution of biosimilars, as this is regulated at the EU member state level.⁴